",isbn:"978-1-80355-367-2",printIsbn:"978-1-80355-366-5",pdfIsbn:"978-1-80355-368-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"d3a491e5194cad4c59b900dd57a11842",bookSignature:" Vladimir V. Kalinin",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11782.jpg",keywords:"Variety of Traits, Historical Remarks, Modern Definitions and Descriptions, Personality Disorders, Comorbid Psychopathology, Depression, Anxiety, Obsessions, Delusion, Treatment of Personality Disorders, Phenomenology of Personality Traits, Delusional Symptoms",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 9th 2022",dateEndSecondStepPublish:"May 12th 2022",dateEndThirdStepPublish:"July 11th 2022",dateEndFourthStepPublish:"September 29th 2022",dateEndFifthStepPublish:"November 28th 2022",remainingDaysToSecondStep:"9 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:'A researcher with over 300 publications in psychopathology, psychopharmacology, neuropsychiatry, and epileptology, a member of the Russian Society of Psychiatry, and the Russian Society of Epileptology. Dr. Kalinin\'s biography is included in Marquis "Who’s Who in Medicine and Healthcare" (2006-2007); Who’s Who in Science and Engineering 2008-2009"; "Who’s Who in the World" (2010, 2011), and in the Cambridge International Biographical Centre.',coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"31572",title:null,name:"Vladimir V.",middleName:null,surname:"Kalinin",slug:"vladimir-v.-kalinin",fullName:"Vladimir V. Kalinin",profilePictureURL:"https://mts.intechopen.com/storage/users/31572/images/system/31572.png",biography:"Vladimir V. Kalinin was born in1952 into a family of physicians in Orenburg (Russian Federation). He obtained an MD from Moscow State Medical Stomatological University in 1976. In 1976-1977 he completed an internship in Psychiatry. 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1. Introduction
Utilization of CO2 becomes more and more important with increasing CO2 emission which causes the global warming and the ocean acidification problems [1, 2]. The huge CO2 emission also relates on depletion of fossil fuels. The conversion of CO2 into useful fuels and chemicals is very urgent to solve the abovementioned problems. The use of biomass instead of fossil fuels is actively researched and partly undertaken [3]. In many chemical laboratories, fixation of CO2 into organic compounds by organometallic catalysts is vigorously studied [4].
Reduction of CO2 with electrons is an attractive chemical conversion to obtain the useful products for fuels and chemical materials. It is so simple that it can be applied to photocatalyses which supply electrons from electron donors such as water. The equilibrium potentials (E0’ V vs. SHE at pH 7) for CO2 reduction are listed in Figure 1 [5, 6]; they are thermodynamic values and tend to positively shift with increasing the numbers of electrons participated. One-electron reduction of CO2 requires very high energy. Furthermore, the product, CO2 anion radical (CO2−∙), is difficult to give useful organic chemicals because it is a very strong reducing reagent to reduce other molecules and recover CO2. Thus, the CO2 reductions with multielectrons are desired; however, their reactions are generally difficult even in the electrochemical reduction. A reason is that the intermediates would release from the surface of the electrode as the products before accepting further electrons. To achieve CO2 reduction with more than two electrons, the catalysts which allow to lower the activation energies are required. In other words, the catalysts can undergo the CO2 reduction at the potentials closed to the equilibrium ones. The two-electron reduction of CO2 produces carbon monoxide (CO) and formic acid (HCOOH). The equilibrium potentials are more negative than the proton reduction to afford H2. Therefore, the catalysts which can selectively reduce CO2 rather than H+ are also desired. Both CO and HCOOH are useful chemicals: CO can be converted into liquid hydrocarbons by using the Fischer-Tropsch reaction [7], and HCOOH which can be readily converted to H2 is a safe storage material for H2 [8].
Figure 1.
Equilibrium potentials for CO2 reduction (E0’ V vs. SHE (pH 7)).
A lot of metal complexes have been researched for the CO2 reduction catalyses [9, 10, 11, 12, 13, 14, 15, 16]. Until now, the metal complexes of Mn [17, 18, 19], Fe [20, 21], Co [22, 23, 24], Ni [24, 25, 26, 27, 28], Cu [29], Mo [30], Ru [31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64], Rh [65, 66], Pd [67, 68], W [30], Re [69, 70, 71, 72, 73, 74, 75, 76], Os [77, 78], Ir [65, 66, 79, 80] have been reported as the catalysts for CO2 reduction. Figure 2A shows the elements of the metal complexes acting as the electrochemical CO2 reduction catalysts. The metal complexes indicated in red include the catalysts for photochemical reduction. Figure 2B shows the examples of the metal complexes as the CO2 reduction catalysts. These catalysts based on metal complexes are sometimes called as “molecular catalysts” because they can be designed on the molecular levels by selecting the metal elements and the ligands. The representative and efficient catalysts for CO2 reduction are nickel(II) cyclam (cyclam: 1,4,8,11-tetraazacyclotetradecane), ruthenium(II) polypyridyl carbonyl complexes and rhenium(I) bipyridyl tricarbonyl complexes. Recently, the complexes with nonprecious metals such as manganese(II) and iron(II) attract much attention. They are abundant and readily available, while they are less durable and efficient as the disadvantageous points.
Figure 2.
Metal complexes reported as CO2 reduction catalysts: (A) the metal elements in the complexes (the elements in the metal complexes for photocatalyses are indicated in red) and (B) the molecular structures.
In this chapter, the electrochemical CO2 reduction catalyzed by the ruthenium complexes as the examples is described. The reduction products are CO and formic acid, while the nickel and rhenium complexes selectively yield CO. Discussion for the catalytic mechanisms is introduced particularly for the factors determining the product selectivity. In the next section, the photocatalytic CO2 reduction assisting by the photosensitizers is described. The reaction procedures, the principles for selecting the photosensitizers and the electron donors, and the photocatalytic mechanisms are summarized. Furthermore, application of the homogeneous catalytic systems to heterogeneous catalyses, which is practically advantageous in the viewpoints of separation of the catalysts from the reactants and the products, is described. In the final section, the artificial photosynthetic systems, which would be realized by utilizing the molecular catalysts, are prospected.
2. Electrochemical CO2 reduction
The representative molecular catalysts based on ruthenium complexes are cis-[Ru(bpy)2(CO)2]2+ (bpy: 2,2′-bipyridine), trans(Cl)-[Ru(bpy)(CO)2Cl2] and the derivatives (Figure 3). They have the bipyridyl ligand which would act as an electron reservoir. The efficient catalysts have the carbonyl ligand, which would draw electrons. It tends to lower the reduction potentials of the metal complexes as well as to lower the overpotentials for the CO2 reduction.
Figure 3.
Ruthenium-bipyridyl complexes as electrochemical CO2 reduction catalysts: (A) cis-[Ru(bpy)2(CO)2]2+ and (B) trans(cl)-[Ru(bpy)(CO)2Cl2].
2.1. Electrochemical analysis
Electrochemical analyses (e.g., cyclic voltammetric measurements) are recommended to know the electrochemical properties of the molecular catalysts. The analyses do not only teach us the reduction potentials of the metal complexes but also show whether the complexes can react with CO2 or not. Figure 4 shows the cyclic voltammograms (CVs) of cis-[Ru(bpy)2(CO)2]2+ in CH3CN or CH3CN/H2O (9:1). The Ag-Ag+ (CH3CN) reference electrode (0.10 M Tetrabutylammonium perchlorate (TBAP) /0.01 M AgNO3 in CH3CN) is used; the potential (0.00 V vs. Ag/AgNO3 (CH3CN)) corresponds to −0.09 V vs. Fc/Fc+ in CH3CN. The CV of cis-[Ru(bpy)2(CO)2]2+ in CH3CN under Ar shows an irreversible reduction wave at −1.3 V vs. Ag-Ag+ (CH3CN) as shown in Figure 4 (black line). The irreversible reduction suggests that the one-electron reduction accompanies with a chemical reaction followed by further one-electron reduction. Such a reaction mechanism is called as electrochemical-chemical-electrochemical (ECE) one. The CV under CO2 is a little different from that under Ar, suggesting that the reduced species react with CO2 (Figure 4, blue line). In CH3CN/H2O (9:1), the CV exhibits a strong cathodic current under CO2 (Figure 4, red line), which corresponds to the catalytic reduction of CO2 in the presence of a proton source such as water. The catalytic reduction currents can be analyzed to estimate the efficiency of the catalyst [20, 81]; however, it should be noted that the cathodic currents do not always exhibit the catalytic CO2 reduction [82]. The electrolyses of the metal complexes under CO2 should be carried out to confirm the catalytic efficiency.
Figure 4.
Cyclic voltammograms of cis-[Ru(bpy)2(CO)2](PF6)2: In Ar (black) or CO2-saturated CH3CN (blue) or in CO2-saturated CH3CN/H2O (9:1) (red) containing NBu4ClO4 (0.10 M).
2.2. Electrolysis
A typical electrolysis cell is shown in Figure 5. The cell for reduction (the side of the working electrode) is separated from the cell for oxidation (the counter electrode) with a membrane such as Nafion. A glassy carbon or a Pt plate is used for the electrodes. The metal complex is dissolved in the reaction solution and acts as the homogenous catalyst. CO2 is bubbled with a needle through the septum before electrolysis. Electrochemical CO2 is carried out in batch mode. Reduction of CO2 occurs on the working electrode at the electrochemical cell. Sampling of the gaseous and liquid phases is performed by a syringe through the septum. The gaseous products (CO and H2) are analyzed by gas chromatography. The liquid product, HCOOH, is analyzed by electrophoresis, ion chromatography or gas chromatography. The electrolysis is carried out by the controlled potential method, where the potential is determined from the electrochemical analysis (e.g., CVs). The chronopotentiometry, in which the current is constant during the electrolysis, is important for the industrial use. However, the results in the constant potential lead to elucidate the catalyses because the electrolysis potential relates on the catalytic species. Thus, almost all the scientific researches adopt the controlled potential electrolyses.
Figure 5.
Electrolysis cell for electrochemical CO2 reduction.
2.3. Electrocatalytic CO2 reduction by cis-[Ru(bpy)2(CO)2]2+
The ruthenium complexes are used as the homogeneous catalysts by dissolving in the reaction solution. The electrolysis of the CO2-saturated H2O/DMF (1:1) solution of cis-[Ru(bpy)2(CO)2]2+ was carried out at −1.50 V vs. SCE with an Hg pool as the working electrode (Figure 6) [62]. The catalyst could selectively reduce CO2 to afford CO and HCOOH, while H2, the reduction product of water, scarcely evolved. As the reaction proceeded, the speed for CO production got slow, but HCOOH production became fast. It was interpreted as the result of the decreasing the proton concentration ([H+]) in the reaction solution by consumption of the proton during the reduction. Actually, the reactions in the buffered solution with H3PO4-NaOH exhibited that the production speeds of the CO2 reduction were unchanged during the reactions. It was the decisive result that HCOOH selectively produced when phenol with the high pKa (ca. 9.95) was used as the proton source. These results suggest that there is an acid-base equilibrium between two intermediates in which one is for CO production and another for HCOOH.
Figure 6.
Plots of the amounts of products vs. the electricity in the electrolysis (−1.50 V vs. SCE) of CO2-saturated H2O/DMF (1:1 v/v) solution containing cis-[Ru(bpy)2(CO)2](PF6)2 (5.0 × 10−4 M) and LiCl (0.10 M) as the supporting electrolyte at room temperature.
Thus, the mechanism involving the equilibrium among the carbonyl complex [Ru(bpy)2(CO)2]2+, the carboxylic acid complex [Ru(bpy)2(CO)(C(O)OH)]+ and the CO2 adduct complex [Ru(bpy)2(CO)(CO2)] was proposed for the catalytic CO2 reduction (Figure 7, left cycle) [58, 62]. All the complexes were isolated, and the crystal structures were characterized [83]. In the mechanism, [Ru(bpy)2(CO)2]2+ is reduced to yield the coordinated unsaturated species [Ru(bpy)2(CO)] with evolving CO. The five coordinated complex reacts with CO2 to afford the η1-CO2 adduct complex, [Ru(bpy)2(CO)(CO2)], in which CO2 coordinates to the metal center at the carbon atom. The electronic structure of the CO2 bound complex still remains unknown. In the original report [62], it is drawn as [Ru(bpy)2(CO)(COO−)]+ in which as electron localizes on the CO2 ligand. In Figure 7, it is drawn as [Ru(bpy)2(CO)(CO2)]0 which is the resonance structure of [Ru(bpy)2(CO)(COO−)]+. The CO2 adduct complex is protonated to give the carboxylic acid complex [Ru(bpy)2(CO)(C(O)OH)]+ and further protonated to recover the carbonyl complex [Ru(bpy)2(CO)2]2+. The carboxylic acid complex could be reduced to yield HCOOH, and the carbonyl complex to produce CO. The proposed idea reasonably elucidates the experimental results that the catalytic CO2 reduction gives CO and HCOOH under protic and less protic conditions, respectively. This idea is also supported by the result that the ruthenium complex derivatives give the CO/HCOO− selectivity depending on the different equilibrium constants [58]. The carbonyl complex reacts with dimethylamine to afford the carbamoyl complex [Ru(bpy)2(CO)(C(O)N(CH3)2)]+, and the electrochemical CO2 reduction in the presence of dimethylamine produces N,N-dimethylformamide (DMF) [84]. It is also an evidence which the carbonyl complex would exist in the catalysis.
Figure 7.
Two proposed mechanisms for CO2 reduction catalyzed by cis-[Ru(bpy)2(CO)X]n+ (X = CO (n = 2); H (n = 1)): Metal-CO2 adduct mechanism and hydride mechanism.
On the other hand, the ruthenium hydride complex [Ru(bpy)2(CO)H]+ is known to react with CO2 to yield the formate complex [Ru(bpy)2(CO)(OC(O)H)]+ [85]. In the conversion, CO2 is inserted into the Ru-H bond. The formate complex can release formate ion (HCOO−) and is considered to be an intermediate for HCOO− production. Based on the results, the hydride mechanism is proposed (Figure 7, right cycle). In the mechanism, the coordinated unsaturated species [Ru(bpy)2(CO)] does not react with CO2 but a proton to yield the hydride complex. The hydride mechanism reasonably explains the CO2 reduction to produce HCOO−. However, it has a couple of problems [16]. One is that the mechanism is difficult to elucidate the CO production. Production of HCOO− may occur through the hydride mechanism, while CO may produce through the M-CO2 adduct mechanism. In this case, the product selectivity (CO/HCOO−) should be controlled by the reactivity difference between CO and H+ with the coordinated unsaturated complex. Under the protic conditions, the selectivity of HCOO− production should be enhanced; however, the selectivity of the catalyses gives the opposite tendency. Thus, the pH in the solution or the pKa value of the proton source dependence on the electrochemical CO2 reduction cannot be explained. Another is that the ruthenium catalyst does not evolve H2 so much in the CO2 reduction. It suggests that the catalyst intermediate strongly binds with CO2 rather than H+.
Nevertheless, the hydride mechanism is supported by many researchers. It is because there are many research works on the CO2 insertion into Metal-H bonds to afford the corresponding metal formate complexes. On the other hand, the research works on the carboxylic acid complex are fewer, and no mechanical pathways of HCOO− production from the carboxylic acid complex are not understood on the molecular levels.
2.4. Electrocatalytic CO2 reduction by trans(cl)-[Ru(bpy)(CO)2Cl2]
Trans(Cl)-[Ru(bpy)(CO)2Cl2] is known to be an efficient catalyst for electrochemical CO2 reduction [58]. The catalytic activity and the product selectivity are similar as these of cis-[Ru(bpy)2(CO)2]2+. Reduction of trans(Cl)-[Ru(bpy)(CO)2Cl2] induces to release Cl− ion to afford the coordinated unsaturated complex. This complex is considered to an intermediate which can bind with CO2; however, it induces polymerization in the absence of CO2 as shown in Figure 8 [86, 87]. The polymer with Ru(0)-Ru(0) bonds is also an efficient electrocatalyst for CO2 reduction [50, 54]. The complex is electrochemically reduced to polymerize on the cathode electrode. The electrode modified with the polymer is moved to another electric cell, and it works in the presence of CO2 as the active electrode for electrochemical CO2 reduction. Researches to make the modified electrode stable have been actively done: introduction of pyrrole groups to the bipyridyl ligand also yields pyrrole polymers to stabilize the ruthenium polymer.
Figure 8.
Electroreductive polymerization of trans(cl)-[Ru(bpy)(CO)2Cl2].
The catalytic reaction mechanisms are also unknown but are considered similar as these of cis-[Ru(bpy)2(CO)2]2+. Machan et al. reported the electrochemical CO2 reduction catalyzed by trans(Cl)-[Ru(6Mesbpy)(CO)2Cl2], which has two bulky groups at 6,6′-positions in 2,2′-bipyridine [35]. The complex does not polymerize because of the steric hindrance. They discussed the reaction mechanisms based on the hydride mechanism (Figure 9). The precursor complex is at the center of the scheme. It is reduced with releasing Cl− ion to yield the coordinated unsaturated species, which does not bind with CO2 but H+ to afford the hydride complex. The hydride complex reacts with CO2 to yield the formate complex, which is reduced to produce HCOO− with recovering the original complex. However, the catalyst mainly produces CO not HCOO−. In the mechanism, the formate complex converts to the carboxylic acid complex and then the carbonyl complex by dehydration. The conversion of the formate complex to the carbonyl complex via the carboxylic acid complex is not known, and therefore further researches are expected.
Figure 9.
A proposed mechanism of electrochemical CO2 reduction catalyzed by trans(Cl)-[Ru(6Mesbpy)(CO)2Cl2].
Homogeneous catalysts are advantageous from the viewpoints of elucidating the catalytic reaction mechanisms compared to heterogeneous ones because the homogenous catalysts can be examined by using many spectroscopic techniques. Nevertheless, the mechanisms of the electrochemical CO2 reduction catalyzed by the ruthenium complexes still remain unknown. There may be potentially many intermediates and pathways in the catalyses, and they depend on the reaction conditions and the subtle difference among the catalyst structures [16, 37].
3. Photochemical CO2 reduction
In the preceding section, the electrocatalytic activities of the ruthenium complexes are introduced. The electrocatalyst can be utilized in photocatalytic systems by combining with a photosensitizer (PS). Figure 10 shows a schematic drawing of the photocatalytic system, in which the excited PS (PS*) receives an electron from an electron donor to afford the one-electron reduced PS (PS−). The PS− is the more powerful reagent than PS*, and it can inject an electron to the electrocatalyst. The catalyst can work similarly as the electroreduction occurs. In this section, the photocatalytic CO2 reduction by the ruthenium complexes is expounded.
Figure 10.
A schematic drawing of photocatalytic reduction by combining a photosensitizer (PS) with an electrocatalyst (Cat.).
3.1. Photosensitizer and sacrificial electron donors
The most common photosensitizer used in photocatalytic CO2 reduction is [Ru(bpy)3]2+ and the derivatives. Figure 11 shows the absorption and emission spectra of [Ru(bpy)3]2+ in acetonitrile. The complex exhibits an absorption band at 400–500 nm, which is assignable to metal-to-ligand charge transfer (MLCT). When excited at the band, the emission at the longer wavelengths is observed. The emission is not fluorescence but room-temperature phosphorescence, which is sensitive to O2. Therefore, the emission spectrum should be carefully measured under deaerated conditions [88]. The lifetime of the excited state of [Ru(bpy)3]2+ is 1.10 μs in acetonitrile [89, 90]. The quantum yield has been recently reevaluated as 0.095 in acetonitrile [91]. The oxidation potential (corresponding to the reducing ability) of the excited state (PS*) is −0.81 V vs. SCE (CH3CN), while this of the one-electron reduced species (PS−) is −1.33 V. As the electrochemical CO2 reduction catalyzed by the ruthenium complexes proceeds under electrolysis at −1.30 V vs. SCE, it requires the reducing ability of PS−. In general, the CO2 reduction requires higher energy than H2 production by reduction of H2O, and therefore, the photocatalytic CO2 reduction does not utilize the excited state but the one-electron reduced species.
Figure 11.
Absorption and emission (phosphorescence) spectra of [Ru(bpy)3]2+ in deaerated CH3CN at room temperature.
To generate the one-electron reduced species PS−, the electron donors can reductively quench the excited state of the photosensitizer. As the reduction potential of the excited state of [Ru(bpy)3]2+ is +0.77 V vs. SCE (CH3CN), the electron donors which can be oxidized at less positive potentials than +0.77 V. Figure 12 shows the examples of the electron donors which are actually used in photocatalytic CO2 reduction [16, 92]. Ascorbate ion (AscH−) can be used in aqueous solution, but amines (triethylamine (TEA) and triethanolamine (TEOA)) cannot work in the presence of water because they are protonated to afford the ammonium ions which cannot give an electron. 1-Benzyl-1,4-dihydronicotineamide (BNAH) is a model compound of NADH in nature. NADH is a two-electron donor and is oxidized to yield NAD+. However, the model compound BNAH cannot give two electrons in the oxidation by the excited state of [Ru(bpy)3]2+ but provides one electron to afford the dimer BNA2. 1,3-Dimethyl-2-phenyl-2,3-dihydro-1H-benzo[d]imidazole (BIH) and the derivatives (e.g., BI(OH)H), which have much stronger reducing power than BNAH, have been recently utilized in photocatalytic CO2 reduction. BIH provides two electrons to yield the oxidation product BI+.
Figure 12.
Examples of the electron donors (D) used in photochemical CO2 reduction.
These electron donors are called the sacrificial reagents because the one-electron oxidized species occur chemical changes or decompose so as to prevent back electron transfer. They are useful in order to investigate the reductive half reaction. However, from the viewpoint of the energy balance, the reduction-oxidation (redox) systems in which water is oxidized and CO2 is reduced are desired.
3.2. Photocatalytic CO2 reduction
Our group have investigated the photochemical CO2 reduction by the system consisting of trans(Cl)-[Ru(bpy)(CO)2Cl2], [Ru(bpy)3]2+ and BNAH as the catalyst, the photosensitizer, and the electron donor, respectively (Figure 13). The catalysis had been carried out in N,N-dimethylformamide (DMF)/water [57, 59]. However, it was indicated that hydration of DMF affording formate became a serious problem in quantifying formate [93]. We proposed the use of N,N-dimethylacetamide (DMA), of which the dehydration does not produce formate but acetate, instead of DMF [39]. Although the photocatalysis strongly depends on the solvent system, the reaction proceeds in DMA/water similarly as in DMF/water.
Figure 13.
Photochemical CO2 reduction catalyzed by trans(Cl)-[Ru(bpy)(CO)2Cl2] with [Ru(bpy)3]2+ (a photosensitizer (PS)) and BNAH (an electron donor).
The catalytic reaction proceeds by receiving electrons from the photochemically driven electron relay system. For two-electron reduction of CO2 to CO or HCOOH, the electron relay cycle has to go round two times when the catalytic cycle turns one time. The electron source is not an electrode, but the reaction had been supposed to proceed according to the same mechanism as in electrochemical reduction. However, it has been recently indicated that in some cases, the reaction mechanisms of the photochemical CO2 reduction are likely different from the electrochemical one [16]. For example, unusual catalyst concentration dependence on the product selectivity (CO/HCOO−) in the photocatalysis has been observed: at high catalyst concentration the selectivity of HCOO− increases [37]. To elucidate the peculiar catalyst concentration effect, the mechanisms as shown in the right cycle in Figure 14 are proposed. At the high concentration of the catalyst, the reduced catalyst forms a dimer, which is proposed to selectively afford HCOO−. The dimer of the complex is similar as the intermediate of polymerization, but it is not detected in the photocatalytic system because the absorption spectrum cannot be conformed due to the overlapped absorption of [Ru(bpy)3]2+. Alternatively, the photocatalytic CO2 reduction by trans(Cl)-[Ru(6Mesbpy)(CO)2Cl2] which does not dimerize because of the steric hindrance of the ligand has been examined. The ruthenium complex selectively produces CO in the photochemical CO2 reduction, and it demonstrates that the dimerization of the catalyst relates on the HCOO− production. It is suggested that the catalyst concentration dependence is not observed in a DMA/ethanol solution. It indicates that HCOO− also produces in the cycle consisting of mono-nuclear ruthenium complexes as proposed for the electrocatalytic CO2 reduction (Figure 14, left cycle) [31].
Figure 14.
A proposed reaction mechanism for photocatalytic CO2 reduction by trans(Cl)-[Ru(bpy)(CO)2Cl2].
The photochemical CO2 reduction catalyzed by trans(Cl)-[Ru(2,2′-bipyridine)(CO)2Cl2] bearing two methyl groups at 4,4′- or 5,5′-positions in the ligand has been recently reported [64]. As the catalytic activities of these complexes at low catalyst concentrations are almost the same, the intrinsic activities are considered to be identical. However, the catalytic activities of these complexes are different at high catalyst concentration, where the rate-determining step is not in the catalytic cycle but in the electron relay cycle: the ruthenium complex with dimethyl groups at 5,5′-positions in the 2,2′-bipyridyl ligand is higher than that at 4,4′-positions. The efficiency of the back-electron transfer from the reduced catalyst to the photosensitizer is lower, or the cage escape yield for the sensitizer-catalyst complex is higher in the 5,5′-dimethyl complex than in the 4,4′-complex.
These phenomena have not been observed in electrochemical CO2 reduction. It is probably because that the homogenous photocatalytic CO2 reduction contains the diffusion process of the electron relay between the photosensitizer and the catalyst. The speed of the electron supply also sometimes affects the reaction mechanisms [16, 37].
3.3. Application to heterogeneous catalysts
Heterogeneous catalysts are industrially important because they are useful for separating the starting materials and the products from the catalyst and can be recovered and reused. The molecular catalysts can be utilized to develop the heterogeneous catalysts. For photocatalysts of CO2 reduction, combining the molecular catalysts with semiconductor [32, 94, 95], metal-organic frameworks (MOFs) [96, 97] or periodic mesoporous organosilicas (PMOs) [98, 99, 100, 101] are actively researched. We have also developed a novel PMO consisting of 2,2′-bipyridyl framework by introducing two different ruthenium complexes as a photosensitizing site (Ru(PS)) and a catalytic site (Ru(Cat)) as shown in Figure 15 [99]. Photochemical CO2 reduction by the PMO catalyst has catalytically produced CO and formate. The product selectivity (CO/formate) becomes large with increasing the ratio of Ru(PS) to Ru(Cat) (x/y). The photocatalysts can be recycled at least three times without losing the catalytic activity, demonstrating that the Ru(PS) and Ru(Cat) units are strongly immobilized on the BPy-PMO framework.
Figure 15.
Photocatalytic CO2 reduction by periodic mesoporous organosilica (PMO) containing two different ruthenium complexes as photosensitizing and catalytic sites.
4. Future prospects
The molecular catalysts are applicable to various photocatalytic systems. Ultimately, our goal is to construct an artificial photosynthetic system. An example is shown in Figure 16. In the system, the electrons are not supplied from the sacrificial electron donor but from water which is the same as in natural photosynthetic system. As the CO2 reduction requires a high potential, two photosensitizing systems would be combined as the Z-scheme mechanism in the natural photosynthesis. In order to realize the artificial photosynthesis, we have to overcome some problems. One is to perform these reactions (water oxidation, photo-induced electron transfer and CO2 reduction, etc.) under the similar conditions or in the separated circumstances. Another is to match the velocities among the reactions; even if the efficient catalyst for CO2 reduction was obtained, the speeds for the water oxidation and the electron supply have to match with that of CO2 reduction.
Figure 16.
A schematic drawing for an artificial photosynthetic system.
There would be many other problems to construct the artificial photosynthesis. However, the real system which can efficiently work has already existed in nature. We will realize it with a lot of ideas to overcome many problems one by one.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology (17K05815). This work was also supported by the PRESTO Program of JST, and a Grant-in-Aid for Scientific Research on Innovative Areas, “Artificial Photosynthesis (AnApple)” (No. 15H00882), from the Japan Society for the Promotion of Science (JSPS).
\n',keywords:"CO2 reduction, artificial photosynthesis, electrochemistry, photochemistry, ruthenium",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/60087.pdf",chapterXML:"https://mts.intechopen.com/source/xml/60087.xml",downloadPdfUrl:"/chapter/pdf-download/60087",previewPdfUrl:"/chapter/pdf-preview/60087",totalDownloads:1876,totalViews:644,totalCrossrefCites:0,totalDimensionsCites:3,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:68,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"April 30th 2017",dateReviewed:"February 12th 2018",datePrePublished:"March 21st 2018",datePublished:"August 16th 2018",dateFinished:"March 21st 2018",readingETA:"0",abstract:"Conversion of CO2 into useful chemicals is attractive as a solution of the fossil fuel shortage and the global warming problems. Reduction of CO2 into carbon monoxide (CO) and formic acid (HCOOH) is also important for obtaining the materials in organic syntheses. There are a lot of studies on the catalysts for electrochemical/photochemical CO2 reduction. Especially, transition metal complexes have actively researched as the molecular catalysts for CO2 reduction. In this chapter, the electrochemical/photochemical CO2 reduction catalyzed by cis-[Ru(bpy)2(CO)2]2+ (bpy: 2,2′-bipyridine) and trans(Cl)-[Ru(bpy)(CO)2Cl2] is described as a representative example.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/60087",risUrl:"/chapter/ris/60087",book:{id:"6186",slug:"carbon-dioxide-chemistry-capture-and-oil-recovery"},signatures:"Hitoshi Ishida",authors:[{id:"210140",title:"Dr.",name:"Hitoshi",middleName:null,surname:"Ishida",fullName:"Hitoshi Ishida",slug:"hitoshi-ishida",email:"ishida.h@kansai-u.ac.jp",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210140/images/system/210140.png",institution:{name:"Kansai University",institutionURL:null,country:{name:"Japan"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Electrochemical CO2 reduction",level:"1"},{id:"sec_2_2",title:"2.1. Electrochemical analysis",level:"2"},{id:"sec_3_2",title:"2.2. Electrolysis",level:"2"},{id:"sec_4_2",title:"2.3. Electrocatalytic CO2 reduction by cis-[Ru(bpy)2(CO)2]2+",level:"2"},{id:"sec_5_2",title:"2.4. Electrocatalytic CO2 reduction by trans(cl)-[Ru(bpy)(CO)2Cl2]",level:"2"},{id:"sec_7",title:"3. Photochemical CO2 reduction",level:"1"},{id:"sec_7_2",title:"3.1. Photosensitizer and sacrificial electron donors",level:"2"},{id:"sec_8_2",title:"3.2. Photocatalytic CO2 reduction",level:"2"},{id:"sec_9_2",title:"3.3. Application to heterogeneous catalysts",level:"2"},{id:"sec_11",title:"4. Future prospects",level:"1"},{id:"sec_12",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Olah GA, Prakash GKS, Goeppert A. Anthropogenic chemical carbon cycle for a sustainable future. Journal of the American Chemical Society. 2011;133:12881-12898. 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Inorganic Chemistry. 2005;44:2326-2336. DOI: 10.1021/ic048779r'},{id:"B76",body:'Hawecker J, Lehn JM, Ziessel R. Photochemical and electrochemical reduction of carbon dioxide to carbon monoxide mediated by (2,2′-bipyridine)tricarbonylchlororhenium(I) and related complexes as homogeneous catalysts. Helvetica Chimica Acta. 1986;69:1990-2012. DOI: 10.1002/hlca.19860690824'},{id:"B77",body:'Chauvin J, Lafolet F, Chardon-Noblat S, Deronzier A, Jakonen M, Haukka M. Towards new molecular photocatalysts for CO2 reduction: Photo-induced electron transfer versus CO dissociation within [Os(NN)(CO)2Cl2] complexes. Chemistry—A European Journal. 2011;17:4313-4322. DOI: 10.1002/chem.201003098'},{id:"B78",body:'Bruce MRM, Megehee E, Sullivan BP, Thorp HH, O\'Toole TR, Downard A, Pugh JR, Meyer TJ. Electrocatalytic reduction of carbon dioxide based on 2,2′-bipyridyl complexes of osmium. Inorganic Chemistry. 1992;31:4864-4873. 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Inorganic Chemistry. 2015;54:4475-4482. DOI: 10.1021/acs.inorgchem.5b00315'},{id:"B83",body:'Tanaka H, Tzeng BC, Nagao H, Peng SM, Tanaka K. Comparative study on crystal structures of ruthenium bipyridine carbonyl complexes [Ru(bpy)2(CO)2](PF6)2, [Ru(bpy)2(CO)(C(O)OCH3)]B(C6H5)4∙CH3CN, and [Ru(bpy)2(CO)(η1-CO2)]∙3H2O (bpy = 2,2′-bipyridyl). Inorganic Chemistry. 1993;32:1508-1512. DOI: 10.1021/ic00060a029'},{id:"B84",body:'Hitoshi I, Hiroaki T, Koji T, Toshio T. Electrochemical reaction of CO2 with Me2NH to afford N,N-dimethylformamide, catalyzed by [Ru(bpy)2(CO)2]2+ (bpy = 2,2′-bipyridine). Chemistry Letters. 1987;16:597-600. DOI: 10.1246/cl.1987.597'},{id:"B85",body:'Pugh JR, Bruce MRM, Sullivan BP, Meyer TJ. Formation of a metal-hydride bond and the insertion of carbon dioxide. Key steps in the electrocatalytic reduction of carbon dioxide to formate anion. Inorganic Chemistry. 1991;30:86-91. 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Effect of water during the quantitation of formate in photocatalytic studies on CO2 reduction in dimethylformamide. Inorganic Chemistry. 2012;51:1977-1979. DOI: 10.1021/ic202121s'},{id:"B94",body:'Sekizawa K, Maeda K, Domen K, Koike K, Ishitani O. Artificial Z-scheme constructed with a supramolecular metal complex and semiconductor for the photocatalytic reduction of CO2. Journal of the American Chemical Society. 2013;135:4596-4599. DOI: 10.1021/ja311541a'},{id:"B95",body:'Nakada A, Nakashima T, Sekizawa K, Maeda K, Ishitani O. Visible-light-driven CO2 reduction on a hybrid photocatalyst consisting of a Ru(ii) binuclear complex and a Ag-loaded TaON in aqueous solutions. Chemical Science. 2016;7:4364-4371. DOI: 10.1039/c6sc00586a'},{id:"B96",body:'Kajiwara T, Fujii M, Tsujimoto M, Kobayashi K, Higuchi M, Tanaka K, Kitagawa S. Photochemical reduction of low concentrations of CO2 in a porous coordination polymer with a ruthenium(II)–CO complex. Angewandte Chemie, International Edition. 2016;55:2697-2700. DOI: 10.1002/anie.201508941'},{id:"B97",body:'Sun D, Gao Y, Fu J, Zeng X, Chen Z, Li Z. Construction of a supported Ru complex on bifunctional MOF-253 for photocatalytic CO2 reduction under visible light. Chemical Communications. 2015;51:2645-2648. DOI: 10.1039/c4cc09797a'},{id:"B98",body:'Wang X, Thiel I, Fedorov A, Coperet C, Mougel V, Fontecave M. Site-isolated manganese carbonyl on bipyridine-functionalities of periodic mesoporous organosilicas: Efficient CO2 photoreduction and detection of key reaction intermediates. Chemical Science. 2017;8:8204-8213. DOI: 10.1039/c7sc03512h'},{id:"B99",body:'Kuramochi Y, Sekine M, Kitamura K, Maegawa Y, Goto Y, Shirai S, Inagaki S, Ishida H. Photocatalytic CO2 reduction by periodic mesoporous organosilica (PMO) containing two different ruthenium complexes as photosensitizing and catalytic sites. Chemistry—A European Journal. 2017;23:10301-10309. DOI: 10.1002/chem.201701466'},{id:"B100",body:'Ueda Y, Takeda H, Yui T, Koike K, Goto Y, Inagaki S, Ishitani O. A visible-light harvesting system for CO2 reduction using a RuII-ReI photocatalyst adsorbed in mesoporous organosilica. ChemSusChem. 2015;8:439-442. DOI: 10.1002/cssc.201403194'},{id:"B101",body:'Takeda H, Ohashi M, Tani T, Ishitani O, Inagaki S. Enhanced photocatalysis of rhenium(I) complex by light-harvesting periodic mesoporous organosilica. Inorganic Chemistry. 2010;49:4554-4559. DOI: 10.1021/ic1000914'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Hitoshi Ishida",address:"ishida@sci.kitasato-u.ac.jp",affiliation:'
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1. Introduction
Cerebellar ataxias constitute a very heterogeneous group of diseases in which the motor incoordination is caused by the dysfunction and degeneration of the cerebellar neurons. Although different causative genes or toxins have been identified and several pathological pathways have been investigated, the treatments for these conditions are still largely palliative. Therefore, it is an urgent need for disease-relevant cellular models for studying disease progression and screening for potential therapies.
The rapid development in the field of induced pluripotent stem cell (iPSC) technology offers the opportunity to combine the genetic authenticity of the patient-derived cellular models with the disease-relevant cell types. Human iPSCs have been generated from a wide variety of easily accessible tissues, including skin and blood cells, using methods which nowadays are safer because they avoid the genomic integration of the viral vectors containing reprogramming factors. The potential of iPSCs to differentiate into any cell type of the body was previously explored by the studies with mouse and human embryonic stem cells (ESCs), which are blastocyst-derived pluripotent populations. Both iPSCs and ESCs may offer direct access to study the cells making the nervous system, but straightforth for disease models are the neurons differentiated from iPSCs, generated from patients with a variety of neurologic or neurodegenerative conditions [1, 2].
Although significant advances have been made, most of the protocols for the differentiation of human PSCs into neurons yield cellular populations which can only partially mirror the functional characteristics detected in vivo. In addition, most of the available neuronal characterization comes from the studies in rodents and we still know little about the phenotypes that the human neurons have in different stages of their development or degeneration. Nowadays, only few protocols generate efficiently specific neuronal classes, such as the midbrain dopaminergic neurons or the cortical neurons, while for the most neuronal types in the human brain, including the neurons of the cerebellum, the efficiency of the protocols is much lower and additional cell selection methods are required.
As it happened for the generation of other human neural or non-neural cells and especially for the generation of the cerebral cells (reviewed in [3, 4]), the improvements in the generation of cerebellar neurons will definitely come from a better knowledge of the human cerebellum and its developmental pathways.
The human adult cerebellum is the second largest brain part (after the cerebral cortex) and contains around 80 billion neurons (which represents four times more neurons than in the cerebral cortex) [5, 6, 7, 8]. These neurons contribute to the complex cerebellar functions, including the control of movements for performing fine-tuning and coordination [9, 10], as well as of cognitive and emotional processes [11, 12]. The morphological and functional organization in the cerebellum, intensively investigated in rodents, is highly conserved across vertebrates [13]. Both human and mouse cerebella contain two lateral hemispheres connected by a region named vermis. The lateral hemispheres are subdivided into lobes and lobules and, together with vermis, covered by a uniformly pliated gray matter forming the cerebellar cortex. Cerebellar neurons have their cell bodies (somas) located in the cerebellar cortex and in the nuclei situated inside the white matter of each cerebellar hemisphere, called deep cerebellar nuclei (DCN). There are four distinctive DCN in mouse (dentate, fastigial, emboliform and globose), while the last two are fused as the interposed nucleus in human [10, 13].
The higher number of lobules in humans makes the cerebellar cortex more expanded relative to mice; in spite of the increase in size, both the volume of the cerebellum as a percentage of the total brain and the ratio of the number of neurons in the cerebellum to the cerebral cortex is remarkably constant across mammalian species, pointing to the concomitant increase of the cerebellum and the cerebral cortex in humans [6, 8, 14, 15, 16, 17].
The morphological organization of the adult cerebellum is schematically presented in Figure 1. The neurons located in the cerebellar cortex form three laminar structures laying between the internal white matter and the external pia mater: the granular layer (GL, named also the inner GL), the Purkinje layer (PL) and the molecular layer (ML). The GL contains the densely packed granule cells, which are the most abundant cell type in cerebellum and in the whole brain, as well as few other cells, such as Golgi cells (with different subtypes, such as Lugano, globular and candelabrum) and unipolar brush cells. PL is a narrow middle zone that contains the large cell bodies of the Purkinje cells, together with the cell bodies of a special type of glial cells named Bergmann glia. The ML contains mainly cell projections, but also a few entire neurons such as the basket cells located near the PL and stellate cells located near the pia mater.
Figure 1.
Cellular composition and organization in the adult cerebellum. The cerebellum contains, from exterior to interior, the cerebellar cortex with 3 layers, the molecular layer (ML), the Purkinje layer (PL) and the granular layer (GL), and the deep cerebellar nuclei (DCN) situated in the white matter (WM). Excitatory (red-orange) and inhibitory (green) neurons are located in the cortex (granule cells (GC), unipolar brush cells (UBC), Purkinje cells (PC), Golgi (G), basket (B) and stellate (S) cells) and in the DCN (E-DCN and I-DCN). GC and UBC receive external afferents via mossy fiber, while E-DCN via both mossy fibers and climbing fibers. PC receive external afferents via climbing fibers and internal afferents via parallel fibers, sending efferents to DCN. BG: Bergmann glia (gray).
In addition to the shape and location of their cell bodies, the cerebellar neurons are characterized by other intrinsic properties included in their neurochemical profiles (neurotransmitters, associated neuropeptides and receptors), electrophysiological profiles and, in the recent years, in high-throughput transcriptional fingerprints. Based on the neurotransmitters used for synaptic communication, cerebellar neurons are set into two main classes: excitatory neurons, which release glutamate, and inhibitory neurons, which release mainly γ-aminobutyric acid (GABA). Excitatory neurons are situated in the cerebellar cortex (granule and unipolar brush cells) and in the DCN. Inhibitory neurons are localized also in the cerebellar cortex (Purkinje cells, Golgi cells, basket and stellate cells) and in the DCN (Figure 1).
Regarding tissue architecture and connectivity, the cerebellar neurons are arranged as repeating units in a highly regular manner, relatively identical in all areas of the cerebellar cortex. Granule cells and excitatory neurons in DCN are projection neurons, while inhibitory neurons in the cortex (Golgi cells, stellate cells and basket cells) and DCN, and the unipolar brush cells are interneurons. Granule cells receive excitatory signals from neurons of the brainstem or spinal cord, mainly with a station in the middle or inferior cerebellar peduncle, via the mossy fiber afferents. The information from ~25 million mossy fibers is dispersed to ∼50 billion granule cells, but each dendrite apparently synapses with a single mossy fiber, in this way promoting combinatorial encoding and enhanced processing of sensory input to the cerebellum. Unipolar brush cells receive sensorimotor signals via mossy fibers, each cell forming a specialized giant synaptic junction with a single mossy fiber terminal. Their axons branch locally within the GL, where an intrinsic system superimposes on the canonical extrinsic mossy fiber system (reviewed in [15]).
The axons of granule cells project to the ML, where they form the parallel fibers, which intercept the dendrites of Purkinje cells at right angles. There are ~200 granule cells per Purkinje cell in mice, while in humans there are 3000 granule cells per Purkinje cell [8]. Purkinje cell bodies form a monolayer in the middle of PL, each neuron sending a monoplane-oriented expansive dendritic tree with thousands of little spines into the ML, while its axon projects towards and connects with one neuron in the DCN. In addition to the inputs from granule cells, each Purkinje cell receives excitatory signals from climbing fibers arising from the inferior olive neurons in the medulla (which receives sensory information from the cortex). Purkinje cells convey the results of the analysis of afferent information to the excitatory neurons in DCN, which form the main cerebellar output. Each excitatory neuron in DCN receives inputs from several Purkinje cells, but also inputs from the spinocerebellar tract via the mossy fibers and from the inferior olive via the climbing fibers. Excitatory neurons in DCN send projections back to the brainstem and to motor cortex via the thalamus [18, 19].
Remarkably, Purkinje cells can exhibit two distinct types of action potential, with simple and complex spikes. The simple spikes represent an autonomous pacemaker activity, with very little variability between spiking intervals, firing in absence of synaptic inputs. The simple spikes can be modulated by inputs from mossy fiber via the parralel fibers. Inhibitory interneurons in the ML, i.e. the stellate and basket cells, also influence circuit topography by making synapses with the dendritic tree and modulating the activity level of Purkinje cells. Additionally, Purkinje cells can evoke complex climbing fiber inputs. Integration of the inputs from climbing fibers and parralel fibers in Purkinje cells generates a unique form of heterosynaptic plasticity, that has been shown to underlie the motor learning [18, 20, 21]. In line with the recent multimodal characterization of the cerebral cortical neurons [22], a deeper investigation of the electrical profiles in human cerebellum is expected from the new Patch-seq techniques [23, 24].
A more extensive neuronal characterization was recently performed by high throughput sequencing, including single-cell sequencing for mouse and human cerebellar tissue [25, 26]. In spite of their quite regular morphology, the cerebellar neurons in each subclass appear as a heterogeneous population, different subsets being defined by several molecular cues, including co-neurotransmitters (e.g. glycine) and neuromodulators (e.g. calbindin, parvalbumin). Markers of some subclasses are related to the position in the cerebellar areas (reviewed in [27]). In addition, a comparative high throughput analysis of mouse versus human cerebellar cells using single cell-RNA sequencing showed that several genes are expressed in human but not in mouse Purkinje cells and confirmed at protein level the expression of novel and specific human Purkinje cell markers, in line with the data from the cerebral cortex [28, 29].
Recent progress in genetic technologies has significantly clarified how the cerebellar cells and their circuits are formed in model organisms, especially in mouse [30, 31, 32, 33]. Remarkable advances were made not only in defining of the molecular phenotypes and the differentiation pathways for most of the neural progenitors, but also in understanding of how these synchronize for forming neuronal circuits. Purkinje cells have major roles also during development [34]. They orchestrate the long lasting neurogenesis of the granule cells, the most abundant local excitatory neurons, and the maturation of the local inhibitory neurons, which reciprocally respond by helping in their own maturation.
The human-specific morphological and functional attributes were intensively studied over the last two decades, including for the development of the cerebellum. Mouse mutants for different genes related to developmental diseases affecting the cerebellum in humans demonstrated a considerable evolutionary conservation of the molecular programs across species, but also revealed some human-specific differences. Recent investigations of the developing human cerebellum have emphasized some differences in the organization of the cerebellar progenitor pools. Other human specific differences have been outlined by the single-cell sequencing of different brain cells, including cells in the cerebellum. These high throughput results point out that we still have much to learn about the human cerebellar development, composition and functions.
To what extent can or could the cellular diversity in the adult human cerebellum, and, in the same time, the spatial precision in its organization in vivo be reproduced by the PSC-related differentiation protocols? Which would be a proper human model for cerebellum development and cerebellar diseases?
The reported strategies for the differentiation of human PSCs toward cerebellar neurons, especially toward Purkinje cells, are reviewed in this chaper, followed by an outlook of their further optimization and diversification by implementing the knowledge from cerebellar development and new cell culture approaches. This outlook incudes an overview of the recent progress made in defining the cell populations in developing mouse and human cerebellum, followed by our current knowledge about their development, which includes pattering, proliferation, neurogenesis, gliogenesis, migration, connectivity and maturation. This knowledge is also the basis for the establishment and optimization of the PSC-derived models for cerebellar ataxias. An overview of the reported in vitro patient-derived iPSC approaches for modeling cerebellar ataxias is presented, followed by an outlook of some challenges that remains to be overcome.
2. Differentiation of pluripotent stem cells toward cerebellar neurons
Over the past 20 years, human PSCs, including the ESCs and the iPSCs [35, 36, 37, 38], have revolutionized the research on human development and diseases, particularly for the nervous system. Considerable progress has been made in converting human PSC into different types of neural progenitors, from which some continued to differentiate toward different classes of neurons, in vitro or after xenotransplantation.
Most of the reported human PSC-based protocols are an adaptation of the protocols that were previously developed for mouse ESCs, which reflect, to a various extent, different stages of neural differentiation in mouse embryo. On this line, the differentiation of the human PSCs is expected to reflect different stages of neural differentiation in human embryonic and fetal stages. Remarkably, recent data have demonstrated that several protocols starting from human PSCs produced authentic neurons and structured brain-like tissues, including the cerebral cortex, the most complex structure in the human brain. However, many questions remain about the extent to which the relative simplistic in vitro settings could reproduce the high complexity of the adult brain structures, both in cell diversity and connectivity (reviewed in [3, 39]).
For the neurons making the human cerebellum, the progress of in vitro differentiation protocols was a lot slower comparing to other neuronal populations, such as the spinal cord motoneurons, midbrain dopaminergic neurons, and glutamatergic and GABAergic cortical neurons, between many others. The main reason is the complexity of the cerebellar development, which was only partially and only recently deciphered (overviewed in the next section), while the developmental mechanisms for the spinal cord, midbrain and cerebral cortex were much faster and deeper investigated [40, 41, 42, 43].
Increasing understanding of cerebellar development has allowed the elaboration of several protocols in the last years, which made the production of some classes of cerebellar neurons possible, with increasing efficiencies. These protocols were implemented in 2D and 3D cell cultures, or in their combination. As for other brain regions, the differentiation protocols include “directed” steps, meaning controlled differentiation by using extrinsic manipulation approaches, but also steps in which the differentiation advances spontaneously. Most of the protocols use morphogens/growth factors or small molecules with similar functions, which are sequentially administered to mimic the environment in vivo.
Two early studies implemented the mouse ESCs differentiation into cerebellar neurons, using different approaches [44, 45], which were followed by several protocols aimed to increase their efficiency. Su et al. [45] used non-adherent ESC cell clusters in serum-free medium supplemented with fibroblast growth factor 2 (FGF2) and insulin. The cellular spheroids, named serum-free embryoid bodies (SFEB, even though they contained mainly undifferentiated cells in this stage), gradually differentiated into more complex 3D cell aggregates containing a mixture of progenitor cells and neurons, which included some granule cell progenitors and few neurons expressing early Purkinje cell markers. Following the same conditions, Muguruma et al. [46] showed that the FGF2-treated neural progenitors presented a broad fate, but some cells organized in tissue-like structures resembling the cerebellum origin in the embryo. These 3D cell aggregates further formed brain organoids, which contained some areas organized as a primitive cerebellar tissue. When cyclopamine, a sonic hedgehog (SHH) antagonist, was added to block the spontaneous ventralization, the proportion of cerebellar cells was increased, including 35–42% Purkinje cell progenitors by day 11 of ESC differentiation. Additionally, this study introduced the selection of the cerebellar progenitor cells, addressing to a cell-surface marker expressed in this population (Kirrel2/Neph3). The selected cells survived and integrated into the mouse cerebellum following in utero transplantation at embryonic day (e) 15.5, but their surviving and differentiation into Purkinje cells in vitro was possible only in co-culture with dissociated mouse postnatal cerebellar cells [47]. Following the same protocol, Tao et al. [48] showed that the cerebellar organotypic slices prepared from mice at postnatal day (p) 6–8 supply an appropriate trophic environment for the differentiation and maturation of ESC-derived Purkinje cells. Remarkably, after 28 days in co-culture, they showed the same characteristics as the neonatal Purkinje cells.
Salero and Hatten [44] succeeded in generating mouse ESC-derived granule cells at a relatively high efficiency by implementing a protocol in 2D culture based on step-related treatments with different morphogens. FGF8, WNT1 and retinoic acid (RA) were used in the first step, while bone morphogenic proteins (BMPs) were used in the next step to obtain the granule cell progenitors, which were next proliferated with SHH and Jagged1 and showed markers expressed in GL in vivo. Again, for differentiation and maturation, granule cell progenitors were co-cultured with either postnatal mouse cerebellar neurons or glial-conditioned medium and the resulted neurons resembled the neonatal counterparts.
The pioneering studies of mouse ESC cerebellar differentiation were next translated to human PSCs and subsequently refined (Table 1). The protocol of Muguruma et al. [46] in 3D culture was applied to human ESC and iPSCs [49, 50, 52]. Human progenitor cells self-organized in polarized neuroepithelium containing around 10% KIRELL2+ cells after 20 days. Muguruma et al. [50] also refined this protocol and followed a long-term ESC differentiation in 3D culture, an approach which resembled the first generation of human brain organoids. They found that the dorsal hindbrain patterning is more efficient for human cells without cyclopamine. Sequential addition of FGF19 and stromal cell-derived factor 1 (SDF1) generated approximately 28% KIRREL2+ cells (representing the progenitors of the cerebellar inhibitory neurons) and 18% ATOH1+ cells (representing the progenitors of the cerebellar excitatory neurons) by day 35. As for the mouse protocol, KIRREL2+ cells were subsequently selected by fluorescence activated cell sorting (FACS) and differentiated into Purkinje cells in co-culture with murine granule cell progenitors. The in vitro differentiation of the KIRREL2+ cells for 10 days generated ~45% Purkinje cell progenitors.
General procedure
Hindbrain patterning
Cerebellar progenitors
Cell selection
Neuronal maturation
References
VZ
RL
3D cell cultures spontaneous IsO induction cerebellar organoids
Reported protocols for the differentiation of human PSCs toward cerebellar neurons.
Other approaches aimed to increase the proportion of human ESC-derived cerebellar cells by applying the hindbrain patterning conditions tested for mouse ESCs [44]. Erceg et al. [53, 55] treated human ESCs aggregates with FGF8b and RA, followed by a manual selection of the neuroepithelial cells organized in polarized structures. This procedure yielded, after further differentiation, a heterogeneous population expressing markers of granule cells, Purkinje cells and glial cells. In a more directed differentiation approach, Sundberg et al. [54] used the WNT agonist CHIR99021, FGF8b and FGF2 for pattering the neuroepithelial cells resulted from the parallel neural induction of human ESCs with dual-SMAD inhibition [56]. The patterned progenitors gradually express the hindbrain, cerebellar and Purkinje cell progenitor markers, such as EN1/2, GBX2, PTF1a, KIRREL2 and SKOR2. Between days 24 and 48 of differentiation, markers of GABAergic phenotype and markers of immature Purkinje cells, such as PCP2, were detected. In order to enrich for the Purkinje cell population, instead of the previously used cell sorting for KIRELL2, Sundberg et al. [54] implemented the THY1+ cell selection, a method previously used to purify mouse Purkinje cells from primary cerebellar cultures [57]. The sorted THY1+ cells further matured into Purkinje cells expressing the early Purkinje cells marker PCP2 (or L7). The same team further optimized the directed differentiation protocol [28], by quantifying the effect of patterning molecules on directing the cerebellar cell phenotypes. They found that the combination of the GSK3 inhibitor CHIR99021 (1.5 μM) for 4 days with FGF8b (100 ng/ml) between days 5 and 12 of differentiation generated the highest proportion of Purkinje cell progenitors. From days 12 to 24, neural cell expressing the cerebellar marker KIRREL2 gave rise to increasing numbers of adjacently located cells expressing Purkinje cell markers. As early as day 35 of differentiation, subpopulations of iPSC-derived cells expressed markers of the primary cerebellar progenitor cells. The postmitotic Purkinje cell marker PCP2 was observed starting from day 18 onward. Flow cytometry analysis showed that ∼23% of cells expressed PCP2 at day 24 of differentiation. A changing element of this protocol was the selection of the immature human PSC-derived Purkinje cells in two steps, a negative selection by GD3 immunopanning and a positive selection by magnetic cell sorting (MACS) with NCAM antibodies [28].
As for the mouse cerebellar neurons, the conditions used for the in vitro maturation of the Purkinje cells and granule cells generated from human PSC were undefined, based on co-culture with different cerebellar tissue-derived populations (Table 1). The maturation into functional Purkinje neurons has so far been achieved in undefined conditions by co-culturing with either cerebellar granule cell precursors isolated from murine embryos [50, 51, 52], or with fetal or postnatal cerebellar organotypic slices [48, 49]. A protocol adapted from Muguruma et al. [50] eliminated the KIRREL2+ cell sorting and employed the differentiation of human cells in co-culture with e18.5 mouse cerebellar progenitors [52]. Again, markers of the cerebellar proliferative zones were detected at early times of differentiation and around 10% Calbindin+ Purkinje cells were detected from day 50 onward. Following long-term co-culture (up to 150 days), these neurons expressed the Purkinje cell markers L7, Calbindin, Aldolase C and LHX5 [50]. In the study of Sundberg et al. [54], the selected Purkinje cells were co-cultured with mouse cerebellar glia and then with mouse granule cells. With this methodology, human PSC-derived Purkinje cells formed synapses with mouse granule cells and had more differentiated morphologies. However, significant electrophysiological activity, comparable with that of Purkinje cells in vivo of the iPSC-derived neurons, was observed only following co-culture with human fetal cerebellar slices [49].
3. Strategies for the optimization of the human PSC-derived cerebellar cultures
Even though the reported protocols have advanced in the generation of cerebellar neuron from human PSCs, they still need a lot of optimization in order to generate homogeneous population of cerebellar neurons in 2D cultures or cerebellar tissue-like aggregated in 3D cultures. Looking at the previous optimizated protocols for generating other neuronal populations, such as the midbrain neurons, the cortical neurons or the cortical organoids, it is relevant to follow again the steps which were gradually applied in order to achieve the efficiency and complexity they offer today (reviewed in [3, 4]). Following this aim, here the development principles of the cerebellar neurons are overviewed, from progenitor specification to neuronal assembles, followed by an outlook of how these principles could be applied for the optimization of the protocols generating cerebellar neurons from human PSCs.
During early embryo development, the human neural tube is formed by the folding of a sheet of neuroepithelium and is progressively closed and regionalized under the control of temporally and spatially coordinated gradients of morphogens secreted by organizer centers. At the end of the neurula stage, corresponding to embryonic day (E) 28, the neural tube is entirely closed and contains, from anterior to posterior, the three primary brain vesicles (forebrain, midbrain and hindbrain) and the spinal cord. Soon after the definition of the midbrain-hindbrain boundary (MHB), cerebellum starts to form at the most anterior and dorsal hindbrain territory. In humans, the cerebellar development is highly protracted, extending from E30 to the end of the second postnatal year. In mice, cerebellum almost completes over a period of around one month, starting from embryonic day (e) 9 and including the first three postnatal weeks (reviewed in [15, 58, 59, 60] (Figure 2). However, as for the whole brain, the mechanisms of cell differentiation and histogenesis in cerebellum are mainly conserved in mammals. While the development of the mouse cerebellum was intensively studied [15, 30, 32, 33, 34, 58, 61, 62, 63, 64, 65], the embryonic and fetal stages in human cerebellar development were only recently described in details [13, 16, 59, 60]. Notably, as for the other parts of the human brain, the embryonic and fetal stages of development are not available for cellular and functional studies, and their histological and clinical images represent only snapshots in time for one individual. Conversely, developmental time-course experiments in mice can be conducted on multiple mice of identical genotypes. These studies revealed that the ontogenesis of all neurons and glial cells in the nervous system, including the ones in the cerebellum, follows the same steps of (1) patterning and specification of the progenitor cells, (2) neurogenesis/gliogenesis and (3) migration, histogenesis, formation of the neuronal circuits and neuronal maturation (reviewed in [15, 27, 58, 61, 66, 67]). However, in contrast to other CNS areas, including the cerebral cortex, in which gliogenesis follows neurogenesis [68, 69], glia generation in cerebellum parallels or precedes the long-lasting generation of the granule cells and inhibitory neurons [15, 30, 32, 65, 68]. Even though the main developmental programs are conserved from mice to humans, some important specie-specific differences responsible for the expansion of the human cerebellum have been recently identified [59, 60]. In the following brief presentation, the main morphological, cellular and molecular events in mouse are complemented with the available information in human.
Figure 2.
Timing and the aligned stages in mouse and human cerebellar development. Embryonic days in mouse (e) and human (E). GW-gestational weeks. NE- neuroepithelium (light blue). The cerebellar ventricular zone (VZ) (blue) is the origin of the inhibitory neurons and glial cells. Inhibitory neurons (green) are the Purkinje cells (PC), Golgi, basket and stellate cells, and the inhibitory neurons in the deep cerebellar nuclei (I-DCN). The rhombic lip (RL) (Lila) is the origin of the excitatory neurons in the cortex (Granule cells (GC) and unipolar brush cells (UBC) and in the DCN (E-DCN). Long-lasting progenitor stages for the GC progenitors (GCP-violet), and inhibitory interneuron and glial progenitors (INP and GP, blue). Long-lasting maturation of inhibitory neurons (light green) and of excitatory neurons (light pink-orange), and gliogenesis (gray) stages.
3.1 Patterning and specification of the cerebellar progenitor cells
Several studies in mouse showed that all cerebellar neurons and glial cells originate from the hindbrain region corresponding to the dorsal (or alar) part (or plate) of the first rhombomere (r1) [30, 70]. The anterior limit of the cerebellum is defined by the MHB, named also isthmus, where an organizer center, named the isthmus organizer (IsO), forms early in development and has a major role in the anterior/posterior (A/P) patterning of the midbrain and hindbrain. IsO formation is preceded by a series of pattering events that start in the forming neural plate, where two transcription factors, Otx2 (Orthodenticle Homeobox 2) and Gbx2 (Gastrulation Brain Homeobox 2) define the primitive anterior and posterior domains, respectively [71]. They are further co-expressed in early IsO and then differentially express in the midbrain and hindbrain domains [72]. WNT signaling has a main role in the A/P patterning of the neural tube but also in IsO induction, showed by the loss of IsO in WNT1 homozygous mutants ([73]; reviewed in [74]). Shortly after the primary brain vesicles formation, Fibroblast Growth Factor 8 (FGF8) secreted by IsO patterns the adjacent territories [71, 75, 76, 77, 78, 79, 80]. Additional A/P patterning by extra-neurally secreted retinoic acid (RA) defines the metencephalic and myelencephalic secondary hindbrain vesicles. The metencephalon expresses the homeobox gene Hoxa1, and formed the first hindbrain rhombomere (r1), where the FGF8 blocks the expression of other Hox genes. Next, the selective expression of negative regulators of the activated Ras–ERK pathway in r1 stops the local action of FGF8 [81]. In parallel with the A/P patterning, whole neural tube is patterned also dorsoventrally (D/V). The main ventralizing factor is Sonic Hedgehog (SHH), which by e9 is produced in the floor plate of the metencephalon [15, 74, 82, 83] and secreted into the neural tube’s lumen, which at this level becomes the 4th ventricle. Consequently, the alar plate of the r1 territory is patterned into the cerebellar domain (anlagen) (Figure 3), while anteriorly situated territory becomes the tectum domain, posteriorly, the r2 domain, and ventrally, the pons domain.
Figure 3.
Stages and distribution of cell populations in mouse early cerebellar development. Formation and differentiation of the cerebellar populations from embryonic day (e) 8 to e16, when all the neuronal populations or their long-lasting progenitors are formed. (A) Between e8 and 12, in the dorsal part of the first rhombomere (r1) of the hindbrain neural tube, the cerebellar ventricular zone (CVZ) (light blue) forms at e9–10, due to the dorsal FGF8 signal and ventral SHH signal, while the rhombic lip (RL) forms at after e10, being visible at the border between the CVZ and the roof plate (RP) (light Lila), due to the BMP signaling from the RP, which forms the choroid plexus epithelium (ChPe) (red). (B) Between e12 and 16, different progenitors arrive in the subventricular zone (SVZ) and mantle zone (MZ) of the neural tube. At e12–14, the Ptf1+ ventricular zone (VZ) of the CVZ primary domain contains the Olig2+ and the Gbx1+ subdomains, which generate the Purkinje cell progenitors (PCP) and the interneuron progenitors (INP, blue) domains, respectively, while the first postmitotic Purkinje cells (PC) already exit the SVZ. The VZ in RL contains Atoh1+ progenitors, which gradually form progenitors of the excitatory neurons in SVZ. They generate first the excitatory neurons for the deep cerebellar nuclei (E-DCN) and at later time points (e14–16), they start to generate the unipolar brush cells (UPC). The RL generates also the progenitors of the granule cells progenitors (GCP-violet), which migrate in waves in the MZ close to the pia mater (PM). In the CVZ, cells representing a subpopulation of the INP domain migrates in the MZ and join the E-DCN in a nuclear transitory zone (NTZ), where they start to differentiate into the inhibitory neurons of the DCN (I-DCN).
Between e9 and e12.5 and, the cerebellar neuroepithelium undergoes morphological changes: the midline remains as a single cell layer and forms the roof plate, while each lateral part forms two primary proliferative zones, known as the origins of the neural populations in the mouse cerebellum: the cerebellar ventricular zone (VZ) and rhombic lip (RL) (Figures 2 and 3) [30]. By e10, the roof plate becomes the second cerebellar organizer center and secretes factors belonging (TGF)-β family, such as the bone morphogenetic proteins (BMPs), the most important dorsalizing factors in the cerebellum, and gradually transforms into the choroid plexus epithelium (ChPe). By e12.5, ChPe additionally produces SHH. Genetic fate mapping proved that the morphogens secreted by IsO, roof plate and floor plate define the cerebellar domains which, in addition to the hindbrain restricted expression of Gbx2, show the differential expression of two basic-helix–loop–helix (bHLH) transcription factors: Pancreatic transcription factor 1 (Ptf1) specifies the VZ domain and Atonal homolog 1 (Atoh1, also called Math1), specifies the RL progenitor domain [15, 58, 61, 84, 85].
Each cerebellar progenitor zone forms subdomains with their own spatial and temporal identities, which produce specific neuronal subtypes. VZ-derived progenitors give rise to all GABAergic neurons and glial cells of the cerebellum. VZ-derived neurogenesis starts at e10.5 and continues untill e17 in mouse. Before the neurogenesis starts (~e9), the VZ progenitor domain corresponds to the neuroepithelial cells localized in the VZ of the r1 neural tube (Figure 3). Most of the earliest Ptf1a + progenitors upregulate Kirrel2/Neph3 and oligodendrocyte-specific bHLH gene Olig2 expression [82, 86], while a small proportion in the early rostral VZ express homeodomain-containing transcription factor gene Gsx1. As the neural tube grows, the neuroepithelial cells gradually transform into radial glial progenitors and a subventricular zone appears evident in the VZ domain (SVZvz in Figure 3). Ptfa1+ and Olig2+ radial glial cells start to express Lhx1, Lhx5 and Skor2, and become Purkinje cell progenitors, located in the SVZvz, which gradually express Neurogenin 1 and 2, start neurogenesis and migrate from the SVZvz. Ptfa1+ and Gbx1+ radial glial cells gradually commit to inhibitory interneuron and glial progenitors. The interneuron progenitors express Lhx1, Lhx5 and Pax2. By e14.5, they become predominant in the SVZvz [87] and soon after start to migrate out of the SVZvz and form transient amplifying progenitor pools. Once all the neurons and transit amplifying progenitors exit the SVZvz, the remaining radial glial cells differentiate into Bergmann glia. The VZ-derived transit amplifying progenitors generate inhibitory interneurons, astrocytes and oligodendrocytes [58].
The neuroepithelium of the RL gives rise to all glutamatergic neurons in the cerebellum (Figures 2 and 3), but also to extracerebellar neurons such as the pontine neurons [66, 70]. RL Atoh1+ neuroepithelial cells situated between the roof plate and the VZ domain start their proliferation after the adjacent VZ progenitors (~e10). Also the RL neuroepithelial cells gradually acquire a radial glial phenotype and are patterned in subdomains, which express the paired box gene Pax6 in combination with the zinc finger genes Zic and the homeobox gene Meis. First, Pax6 and Meis2 expressing progenitors commit to neurogenesis, when they gradually express Tbr2 and Tbr1 and generate the glutamatergic neurons in DCN. Later, the remaining RL progenitors co-expressing Pax6, Meis1, Zic1/2 and Barhl1 commit to granule cell progenitors, in parallel with the unipolar brush cell progenitors, which upregulate the Tbr2 expression, downregulate Pax6 expression and become unipolar brush cells [15, 88].
The cerebellar proliferative zones in human embryos have been only recently investigated. The human cerebellar VZ (gradually forming the SVZvz) undergoes massive expansion which covers the second month (E30–56), afterwards extinguishing its proliferative potential and remaining as a single cell layer. Conversely, the RL germinal zone remains small during the peak expansion of the VZ progenitors, but starts a significant expansion at around gestational week (GW) 11, when it forms the SVZRL, which persists long after birth [59, 60].
GABAergic phenotypes. Cerebellar inhibitory neurons, including Purkinje cells and interneurons (Golgi, stellate, basket and inhibitory neurons of the DCN) originate from different subdomains in cerebellar VZ (Ptf1a+), in different waves (Figures 2 and 3). Purkinje cell progenitors (expressing Skor2, Lhx1/5 and Corl2) gradually express Neurog1/2 and start neurogenesis, which in mouse is completed at e12.5. Once in the postmitotic stage, Purkinje cells start a short distance radial migration alongside the radial glial processes toward the mantle zone where they stack in a transient multilayered structure named the Purkinje cell plate and gradually express markers such as Purkinje cell protein 2 (Pcp2, named also L7), Pcp4 and Calbindin 1 (Calb1) [15, 64]. In postnatal stages, due to extensive cerebellar expansion, multilayered Purkinje cells gradually form a monolayer while each neuron starts the development of its characteristic extensive and flattened dendritic arbor and the expression of mature markers synaptic markers [30, 58, 89].
In humans, all Purkinje cells are generated before the 8th GW, which places them among the earliest-born central neurons. They start to migrate at E44 outwards from the VZ along radial glial projections to the pial surface. A broad Purkinje cell multilayer extending in the mantle zone is evident between the GW 10 and 13 GW, while a monolayer distribution is achieved by GW 20–24 (Figure 2). Human Purkinje cells start to develop their characteristic extensive and flattened dendritic arbors and long axons in the early fetal stages, their final maturation being achieved postnatally, in a 6-fold longer period than in mice [59, 60, 90, 91].
Contrary to the Purkinje cells, which are postmitotic already into the cerebellar SVZvz, the Gbx1+ progenitors expressing the paired homeobox gene Pax2 migrate in several waves from the SVZvz to the mantle zone, where they start to express the neurogenic genes Neurog1 or Ascl1 and differentiate into Pax2+ interneurons. In the first wave (from ~e10.5), the interneuron progenitors migrate to the rostral end of the cerebellar anlage in a Nuclear Transitory Zone (NTZ), which is transient zone for the DCN assembly [15]. After the progenitors settle near the already established excitatory neurons, they produce the inhibitory interneurons of the DCN. In later stages of development, NTZ is gradually organized into distinct DCN. In the second wave (from ~e13.5), the interneuron progenitors migrate to the Purkinje cell multilayer, continue their migration in the developing white matter and postnatally reach the developing granular layer where they generate postmitotic Golgi cells. At later stages, interneuron progenitors migrate radially in the white matter, continue to proliferate in a transit amplifying center and eventually generate the stellate and basket cells in the ML [78, 92]. In parallel with the late interneurons progenitors, the progenitors of astrocytes and oligodendrocytes continue to proliferate in the developing white matter (Figure 2).
Glutamatergic cerebellar neurons (excitatory neurons in DCN, granule cells and unipolar brush cells) originate from different subdomains of the RL, in different waves (Figures 2 and 3). The first cells leaving from the RL are the newborn excitatory neurons in DCN. Next, the granule cell progenitors migrate in waves out of the RL, where they continue the proliferation. In the first wave (e10.5–12.5), discrete subpopulations of rostrally situated Atoh1+ cells gradually upregulate Pax6, Meis2, Lhx9 Tbr2 and Tbr1 and become newborn glutamatergic neurons, which migrate rostrally and tangentially to the NTZ [15, 88, 93]. The allocation of a temporal framework of different DCN components is accompanied by a characterized sequence of transcriptional maturation that results in the first born neurons for the lateral nucleus (projecting to midbrain and thalamus), followed by neurons for the medial (fastigial) group.
The second wave covers middle to late embryonic stages, when Pax6+ granule cell progenitors leave the RL, migrate out toward the pial surface and undergo a prolonged expansion in a secondary germinal zone, or a second transit amplifying center, named the external granular layer (EGL) [64]. Granule cell progenitors retain the expression of Atoh1 and migrate into the mantle zone where they express Tbr2 and continue to proliferate to form the EGL [88]. During the early postnatal period, multiple mitogenic pathways expand the EGL. Peak EGL proliferation occurs around p7 and is complete by p15 (Figure 2). The main mitogen is the SHH, secreted by the underlying Purkinje cells [94], but also Jag1, a ligand the Notch2, acts locally in the EGL [95]. Exponential granule cell proliferation in the EGL drives cerebellar growth and foliation [96]. BMP4 and WNT3 secreted by the ChPe promote cell-cycle exit and neurogenesis [15]. The postmitotic granule cells downregulate Atoh1 and upregulate NeuroD1 [15]. Newborn granule cells migrate tangentially within the EGL and then exit the EGL migrating radially inwardly along Bergmann glial fibers, trailing a long T-shaped axon behind, interact with the flat, elaborate dendrites of Purkinje cells and form the parallel fibers in ML. Migrating granule cells settle below the developing PL to form the internal granule layer (IGL, corresponding to the adult GL), achieving the final laminar arrangement of the mature cerebellum, from where they extend dendrites to form synapses with mossy fiber afferent axons [15, 58].
Unipolar brush cell differentiation parallels the granule cell progenitor waves (Figure 2). Unipolar brush cells are born starting with e13.4, while continuing to p0–1. Progenitors of the unipolar brush cells express Wnt1 early in development (e10.5–13.5), but this expression is downregulated before they migrate from the RL. The newly generated neurons remain in the RL for an additional 1–2 days, after which they exit RL and migrate dorsally through the white matter to their final destination. Most unipolar brush cells reach the IGL by p10, several days before granule cell neurogenesis is complete. Their final maturation occurs between p2 and p28, which seems to coincide with the establishment of the first synaptic contacts with external mossy fibers [15, 27, 88].
3.2 Coordinated formation of the cerebellar circuits
The successful construction of the neuronal circuitry relies on the coordinated generation of functionally opposed neurons. Accordingly, the differentiation programs of cerebellar excitatory and inhibitory neurons are interdependent and defined as the coordinated integration of the VZ and RL-derived lineages in local circuits, in both the cortex and DCN. For the DCN, the cell fate of the excitatory neurons appears determined at the RL, in a temporal pattern, while the interneuron progenitors migrate, differentiate and integrate in the NTZ after receiving local signals from the excitatory neurons.
Purkinje cells have a remarkable capacity to regulate developmental events by sending SHH signals bi-directionally. Starting at e16.5 and continuing throughout adulthood, SHH expression in cerebellum is restricted to Purkinje cells and Bergmann glia [97]. Dendritic-derived SHH drives the granule progenitor cell proliferation, while axon-derived SHH disseminates to the neonatal white matter and contributes to the expansion of the VZ-derived progenitors for the late-born interneurons and glial cells during the postnatal period [98]. Additionally, Purkinje cells are critical for the terminal differentiation and morphogenesis of the interneurons in the ML, the basket and stellate cells. On the other side, signaling from differentiating granule cells influences the planarity and the elaborate branching pattern of the Purkinje cell dendritic tree, which occurs from p5 to p15 [99, 100]. Additionally, the dendritic differentiation of the interneurons in ML is sensitive to the granule cell-derived inputs, including BDNF signaling [15].
In the third trimester and postnatally, human cerebellum undergoes its major growth, primarily due to the prolonged expansion of the granule cell progenitors. By 10–11 GW, streams of cells which form the external GL (EGL) were observed along the pial surface connecting to the RL. Due to extensive EGL proliferation, human cerebellum increases 5 fold in size between GW 24–40 [90]. Differentiation and maturation of the human cerebellar neurons progress mainly as in the mouse, but there are some species-specific features. Foliation correlates with EGL proliferation and increases dramatically between GW 20–32, as the cerebellum rapidly increases in size and volume. The formation of the Purkinje cell monolayer coincides with the peak of EGL proliferation [89, 90]. The human cerebellar cortex still has a prominent EGL at birth. EGL gradually decreases in thickness as a result of migration of granule cells into the internal GL. By the end of the second postnatal year, EGL is depleted while the thickness of the molecular layer and the length of the PL increase, concomitant with the increasing cerebellar volume [89, 90]. To date, there are few studies about the development of the human interneurons, both inhibitory and excitatory, which represent a minority comparing to the granule cells, but with a major role in the maturation of Purkinje cells and circuit formation [15, 34, 58, 91, 101].
In addition, the single-cell sequencing techniques have been applied for analyzing different stages of mouse cerebellar development [62, 102]. Carter et al. [62] performed single-cell RNA-sequencing and unbiased classification of around 40 thousand murine cerebellar cells from eight embryonic samples (at e10-e17) and 4 postnatal samples (at p0, p4, p7 and p10). Such approach allows for a more comprehensive detailing of the transcriptional and cellular heterogeneity among lineages of interest and can provide a valuable resource for answering further questions related to cerebellar development and diseases. In a similar study, Peng et al. [102] analyzed around 20 thousand cells from mouse postnatal cerebella and looked in addition to the dynamics of interneuron differentiation but also mitochondrial markers and ataxia risk genes. In a complementary approach, gene expression in the postnatal stages of mouse cerebellar development were analyzed by Buchholtz et al. [28] in Purkinje cell populations selected from mice expressing a Egfp-Pcp2 reporter gene. Again, the dynamics of different pathways of mitochondrial and autophagy genes correlated with the developmental stages of Purkinje cells, which suggest their implication in several neurodevelopmental diseases.
3.3 From development of the cerebellum to the optimization of the human PSC differentiation protocols
There are several steps to be considered for the cerebellar protocols, which practically cover all the developmental stages: from neural induction and dorsal hindbrain patterning to the patterning and proliferation of the VZ-like and RL-like progenitors, to the neurogenesis of the selected progenitors, and lastly to the maturation of the neurons and the formation of the neuronal circuits. Are the previously used neural induction and early patterning conditions (in both 2D and 3D approaches) optimal for the generation of progenitors similar to the ones in the dorsal r1 in the neurula stage, which represent the origin of the neurons making the cerebellum? Are the previously used conditions optimal for the uniform generation of early VZ and RL progenitors? Which factors and what timing would be necessary for a uniform patterning towards VZ or RL subpopulations? Which conditions would be efficient to produce a uniform neurogenesis from different progenitors? What would the defined conditions for the neuronal maturation be? How can the neuronal maturation be faster? How can other neuronal subtypes, such as the interneurons in the cerebellar cortex and in the DCN, be generated uniformly and efficiently?
Some recent strategies were successful for the optimization of the protocols for the cerebral neurons and cerebral organoids. It remains to be checked whether these strategies can be extrapolated for the cerebellar cultures. Again, the solutions may come from the development principles. The main traiectories that could be followed from the human iPSC to the neuronal cell types contained in the cerebellum are outlooked in Figure 4 and detailed in the following paragraphs.
Figure 4.
In vitro trajectories from human induced pluripotent stem cells to cerebellar neurons by combining the differentiation protocols and the developmental principles. The differentiation conditions for some stages (meaning the combination of extrinsic factors, their concentration and time of action in the protocol) are previously established. However, for several steps, it remains to be established which treatments are necessary for patterning and proliferation of progenitor subpopulation in VZ and RL and in the secondary proliferation domains. Some factors which are known to act in the mouse cerebellar development could work also for the patterning and proliferation of human progenitor cells, but many question marks remain. These questions address both the treatments and the specific markers for subpopulation of progenitor cells and neurons.
Improving neural induction and hindbrain patterning. The first step for all the protocols regarding the neural differentiation of human PSCs implies the removing of the pluripotent cell proliferation factors, such as FGF2 and TGFβ. The additional use of several inhibitors such as BMP/Activin/TGFβ pathway inhibitors, alone (such as Noggin) or in combination (dual-SMAD inhibition by small molecules such as dorsomorphin or LDN and SB431542) [56], significantly increased the yield of neural induction in human PSCs cultured in serum-free medium, both in 2D and 3D systems [40]. Shortly after neural induction, human PAX6+ neuroepithelial cells acquire a primitive anterior identity, expressing OTX2, but no more caudal markers, like EN1, GBX2, or HOX genes [56, 103]. However, this anterior phenotype is transient and, depending on the presence of added or endogenously secreted morphogens such as WNTs, FGFs, and RA, neuroepithelial cells take on a definitive regional identity [41, 104, 105, 106].
Some previous protocols used FGF2 for amplifying the neuroepithelial population and showed that, although an anterior phenotype is kept for a few passages in the presence of FGF2, longer exposure gradually patterns human progenitors toward midbrain and hindbrain fates [105, 107, 108]. FGF2 was used by Muguruma et al. [50] for inducing a brought midbrain-hindbrain patterning, including the IsO-like cells, in 3D spontaneously differentiating human PSCs in serum-free medium, for a time approximating the MHB formation in human embryos. However, the reproducibility of this protocol is limited and the efficiency of the neural induction and pattering was not investigated, many cells in the 3D clusters could present a more anterior phenotype (and maybe non-neural phenotypes). Watson et al. [52] proposed the parallel neural induction and hindbrain patterning by using FGF2 in combination with the SMAD inhibitor SB431542 for around 20 days. Even though it showed an increased expression in hindbrain and cerebellar markers, yet the efficiency and the selectivity of this approach was not reported.
The implementation of WNT signaling was shown to increase the midbrain and hindbrain patterning and reduce the spontaneous forebrain patterning in human PSC-derived neural cultures [28, 41, 54, 109, 110]. In Kirkeby et al. [41] and Kirkeby et al. [110], neural induction with dual-SMAD inhibition and pattering were applied in parallel for 9 days. The GSK3 inhibitor CHIR99021 was used at 1–2 μM concentration for patterning the anterior r1 fate. Following this protocol with some modifications, Sundberg et al. [54] applied the neural induction and hindbrain patterning by WNT in the same time, for 12 days, with noggin and 1.7 μM CHIR99021, while in a following study coming from the same group [28], neural induction and patterning with CHIR99021 1.5 μM was applied for only 4 days. In both studies, FGF8b (100 ng/ml) was added from day 4 to day 12 of differentiation, while FGF2 applied at day 10–12 in Sundberg et al. [54] was excluded in the next protocol [28]. However, the resulted cell populations in both studies were not directly phenotyped, but after 16 or 32 days of differentiation, when they contained KIRREL2+ or THY1+ cells, respectively, which were selected by FACS. Further optimization for neural induction and hindbrain patterning requires a deeper investigation, including negative markers for forebrain, midbrain, hindbrain (excepting the r1), and ventral markers (especially for the r1). The dorsal r1 cells should concomitantly and uniformly express GBX2 and EN1/2. Obviously, reporter lines for different genes expressed solely in r1, such as HOXA1, would be very useful tools.
In addition, a study using human hindbrain tissue from embryos at GW 5–7 showed that the hindbrain neuroepithelial cells were stably expandable in FGF2 and EGF conditions, but the short treatment with FGF8 and WNT (for 1 passage) hugely increased the expression of GBX2, EN1 and EN2 [111]. A deeper investigation of the human embryonic dorsal hindbrain tissue could provide hints for the optimization of the human PSC differentiation protocol toward cerebellar cells. The human embryonic hindbrain neuroepithelial cells can be further patterned in vitro by BMPs (BMP6, BMP7 and GDF7) and WNT3A to RL progenitors (ATOH1), which generated granule cells after transplantation into the rat cerebellum [111]. Some additional hints are revealed by the pattering of the human embryonic hindbrain tissue. ATOH1 was not expressed if FGF8 was added together with BMPs or if FGF2 and EGF were maintained, FGF signaling appearing to counteract the BMP stimulation [111]. The same factors were applied for the RL patterning from human PSCs (reviewed in [40]). It appears clear that ATOH is not expressed by default, but only after BMP signaling, in spontaneous or directed differentiation approaches. Again, developing human PSC reporter lines for ATOH and a deeper phenotypic investigation, including negative markers such the ones express in vicinity of the RL, (e.g. in pons, tectum and neural crest), would be of great help. The same approach is necessary for the optimization of cerebellar VZ progenitors, which are favorized by FGFs and SHH treatments. It remains to be established which treatments with extrinsic factors (combination, concentration and time) are necessary for patterning and proliferation of progenitor subpopulation in VZ and RL, as well as out of them, in the secondary proliferation domain, as long-term proliferative populations (such as granule progenitor cells, interneuron progenitor cells and glial progenitor cells). Some factors known to act in the mouse cerebellar development could work also for human progenitor cells, but many question marks remain. These questions address both the treatments and the specific markers for subpopulation of progenitors and neurons (Figure 4).
Increasing maturation of the cerebellar neurons in defined conditions. One of the most consistent observations about human PSC-derived neurons is that they mature relatively slow and often incomplete (reviewed in [3]). An obvious reason is the time in culture: human PSC-derived Purkinje cells are usually kept in culture around 4 months, while they need over 2 years for maturation in vivo. An important challenge is the long-term culture and maturation of human PSC-derived cerebellar neurons without the presence of mouse cell/tissue co-cultures. Mature phenotypes of PSC-derived Purkinje cells and granule cells have so far only been demonstrated in co-culture or, more convincingly, by transplantation of differentiated cells into mouse cerebellum. While some of the in vitro and transplantation procedures demonstrated the potential of the PSC-derived neurons to mature into functional cerebellar neurons, they also highlighted the need to better understand the factors that promote their maturation. Significant variability in the efficiency to obtain functional Purkinje cells using different feeder cell sources was reported. For instance, feeder-free and co-culturing with rat granular progenitors failed to sustain Purkinje cell maturation and survival, while co-culture with rat cerebellar slices sustained Purkinje cells that nevertheless were devoided of any action potential or spontaneous post-synaptic currents. In contrast, co-culture with human fetal cerebellar slices resulted in electrophysiological active Purkinje cells [49], suggesting that human specific factors, as well as interactions with glial cells [112] are needed for proper maturation. The use of the co-culture system has limitations per se, feeder cells introducing inherent variability to the procedure [49]. A growing number of methods for reverse-engineering specific cellular micro-environments and the cells and molecules which constitute these [113] will definitely extend into the cerebellar field. It is likely that the combination of these technologies will help in elucidating key conditions for long-term survival and maturation of PSC-derived cerebellar neurons.
Another approach can come for the optimization of long-term cultures of cerebellar organoid, in line with the extensively investigated field of cerebral organoids [39]. As shown in different previous reports, functional synaptic connections are necessary for maturation and activity of the human PSC-derived neurons, which include glia and target neurons, all of these could be provided in the same cerebellar organoid.
Again, one limitation for most of the human PSC-derived neurons, as for the human neurons in general, is the lack of transcriptomic signatures, to rigorously identify specific types of neurons and to compare their development across species. A recent Metagene projection analysis of global gene expression patterns revealed that differentiating human PSC-derived Purkinje cells share classical and developmental gene expression signatures with developing mouse Purkinje cells. Remarkably, it revealed that the human PSC-derived Purkinje cells matured in co-culture for around two months are closest to late juvenile (p21) mouse Purkinje cells, suggesting that they are relatively mature. Gene expression profiling also identified human-specific genes in human PSC-derived Purkinje cells. Protein expression for one of these human-specific genes CD40LG, a tumor necrosis factor superfamily member, was confirmed in native human cerebellar tissue, arguing for the bona-fide nature of the human PSC-derived cerebellar neurons [28]. Obviously, the routine applications of the single-cell transcriptomics into the optimization steps of the human PSC-derived cerebellar differentiation protocols will hugely contribute to the progress in the field.
4. iPSC-derived models for cerebellar ataxias
The iPSC technology together with the cerebellar differentiation protocols offer the opportunity to indirectly generate and to directly study the most affected cells in patients with cerebellar ataxias, the cerebellar neurons. As schematically presented in Figure 5, somatic cells such as skin fibroblasts or white blood cells obtained from patients are reprogrammed into iPSCs, which can be theoretically differentiated into any type of neurons. Ideally, the neuronal differentiation should address the most affected subpopulation in each disease, by following the existing protocols or optimized protocols in the desired direction (using development principles and combining efficient selection methods). Remarkably, for the inherited ataxias, the patient iPSC-derived neurons express the disease mutation in the authentic genetic background and cellular environment, which is not the case in the animal models.
Figure 5.
From ataxia patients to neuronal disease models. Somatic cells from patients with cerebellar ataxias are reprogrammed into induced pluripotent stem (iPS) cells, which can be genetically modified in order to correct the mutation. Patient and control/corrected iPS cells can be differentiated into neurons that are relevant for the cerebellar diseases, such as Purkinje cells. Additional stress or forced aging can be equally applied to the patient and control/corrected neurons or their progenitors, in order to amplify the phenotypic differences resulted from the ataxia’s specific mutation.
The neuropathological events in hereditary cerebellar ataxias affect both cerebellar and extracerebellar territories. Nevertheless, degeneration and ultimate loss of cerebellar neurons is a neuropathological hallmark in cerebellar ataxias. The affected cerebellar neurons and the responsible genes for several cerebellar ataxias are presented in Table 2. Spinocerebellar ataxias (SCAs) are a family of over 40 currently described late-onset dominant diseases, manifesting clinically at middle age and gradually progressing with neurodegeneration in cerebellum and other CNS areas, [136, 137, 138, 139] while in other genetic ataxias, such as the autosomal recessive Friedreich ataxia (FRDA) and ataxia-telangiectasia (AT), the disease manifests a lot earlier and, in addition to the nervous system, extraneural territories are affected [137, 138]. FRDA is considered a multi-systemic condition, including central and peripheral neuropathies, diabetes and cardiomyopathy [140, 141].
In cerebellum, SCA1, SCA3 and FRDA involve mainly the DCN, especially the dentate nucleus, but also extracerebellar territories such as the Clarke’s column, which present with severe neuronal loss (reviewed in [142]). SCA2 predominantly affects the pontine nuclei, while the Purkinje cells and DCN seem to be secondarily affected. SCA31 is relatively restricted to the Purkinje cells. Although Purkinje cells are predominantly involved in SCA6, degeneration is evident also in the dentate nucleus and granule cells. Therefore, patients with SCA6 show more severe ataxia than those with SCA31. Several SCA subtypes have CAG repeat expansions in the coding region of different genes (http://www.scabase.eu/; [143, 144, 145, 146]), resulting in PolyQ elongations in the respective proteins, the elongation size being correlated with the intensity of clinical manifestations. In other SCAs (SCA12, SCA31 and SCA36) or non-SCA monogenic ataxias, such as FRDA, the repeat expansion is intronic, but also in these diseases the cerebellar dysfunction is correlated with the elongation size [147].
Modeling these human genetic disorders in mice has reproduced to a certain extend the neuropathological aspects and has provided some insights into disease mechanisms. Many disease mechanisms that have been explored in mouse models are expected to be recapitulated in patient iPSC-derived neurons. However, some ataxias could not be modeled in mice using the same mutation as in the patients, suggestion that the human-specific environment is essential for the disease to develop. Additional mechanistic understanding of the network of events produced by the mutation is crucial for the development of effective therapies, as none of the cerebellar ataxias is yet curable, treatable or preventable [143, 145, 147, 148, 149].
For modeling cerebellar ataxias, the iPSC-based models present three main advantages. First, most of cerebellar ataxias are monogenic diseases. Second, neurons bearing the mutation, which are not directly available from patients, can be generated in vitro from the patient iPSCs. Third, the human neurons generated in vitro seem to acquire a molecular profile close to the postnatal age in mouse, as in the previously mentioned Metagene analysis of key gene pathways, which showed that the human Purkinje cells generated in vitro have the closest molecular expression with the Purkinje cells in p21 mouse cerebellum [28]. As for many mouse models for cerebellar ataxias a disease phenotype was found close to this age, the in vitro generated human neurons are expected to behave similarly and to reveal the disease phenotype in early stage of maturation.
However, as presented in Table 2, relatively few studies have succeeded in generating iPSC-based models for cerebellar ataxias. An additional important question for the iPSC-based models is to what extend the mutated gene is expressed in the neurons generated in vitro. The most vulnerable and affected cells are neuronal subpopulations, most of them being located in cerebellum. From the reported iPSC-derived models, only a very few implemented the cerebellar differentiation protocols, including the pathways for generating the specific cerebellar cells affected in disease.
A handful of studies published to date addressed iPSC models of PolyQ SCAs (such as SCA1, 2, 3, 6, 7 and 12), non-PolyQ SCAs (such as SCA36 and 42), and other ataxias (such as FRDA and A-T). Most of the iPSC-based models used a generic differentiation towards the neural lineage, as opposed to the generation of specific neuronal subtypes, and very few characterized the neuronal phenotypes. The only reported iPSC-derived models addressing the cerebellar neurons were for SCA6 [51], SCA42 [127] and A-T [135].
For SCA1 and SCA12, only the generation of patient-derived iPSCs were until now reported [114, 115, 119, 125]. Several other SCA models have already addressed the neural phenotypes. SCA2 was modeled by Xia et al. [116] and by Chuang et al. [117] using patient iPSC-derived neural progenitors and central neurons. No cerebellar protocol has yet addressed SCA2, in which both Purkinje cells PCs and DCN neurons are affected. Whereas patient and control fibroblasts showed comparable levels of expression of the disease-causing protein Ataxin-2, its expression was decreased in patient iPSC-derived neural stem cells, which survived shorter in cell culture. Chuang et al. [117] reported that SCA2 neurons exhibited a glutamate-dependent disease phenotype, which are suppressed by anti-glutamate drugs and a calcium stabilizer treatment.
One of the first studies using the generation of neurons from patient iPSCs addressed to SCA3, also called Machado-Joseph disease (MJD) [118]. In this model, neuronal excitation by glutamate promoted an increase in intracellular calcium concentration and proteolysis of Ataxin-3, triggering its aggregation—a hallmark of the disease in patients. This intraneuronal aggregation, (which was also found to depend on sodium and potassium channel function, as well as on ionotropic and voltage-gated calcium channel function), was abolished by calpain inhibition, pointing to a key role of this protease in Ataxin-3 cleavage. Furthermore, intracellular aggregations were not observed in patient iPSCs, fibroblasts or iPSC-derived glial cells, providing a clue for the neuron-specific phenotype observed in SCA3 patients. Hansen et al. [120] differentiated the SCA3 patient-derived iPSCs further into hindbrain neurons that expressed GBX2 and HOXA2. They reported that glutamate loading or calcium increase by ionomycin did not induce Ataxin-3 accumulation in these hindbrain neurons. It remains to be investigated whether this discrepancy comes from a difference in cell types or in the applied protocols. In another study [121], SCA3 iPSCs differentiated into NeuN-positive (postmitotic) neurons showed accumulation of Ataxin-3 in the absence of stress. The activation of autophagy by rapamycin was effective for degradation of Ataxin-3, suggesting that autophagy could be a key for development of therapeutic treatments. Chuang et al. [117] reported that SCA3 iPSC-derived neurons again showed glutamate-dependent phenotypes, which were suppressed by anti-glutamate drugs. Ouyang et al. [122] applied gene editing techniques for the deletion of the expanded CAG in the ATXN3 gene in SCA3 patient-derived iPSCs, which were further characterized. Such corrected iPSCs will be useful for SCA3 isogenic models. However, no further studies have addressed SCA3 iPSC-derived cerebellar neurons and a directed protocol for the DCN neurons, the most affected in SCA3, is not yet available.
SCA6 is a very interesting case, first, by being one of the three diseases in which patient iPSC-derived cerebellar neurons were generated to date, and second, because of the bicistronic nature of the affected gene, CACNA1A. It encodes the α1A subunit of P/Q-type voltage-dependent calcium channel Cav2.1, and the α1ACT, with an identical sequence with the PolyQ bearing C-terminal segment of the longest isoform of α1A [150]. In addition, the gene is expressed mainly in neurons, contrary to the other ataxia-related genes, that are ubiquitous expressed. Utilizing the differentiation method for the cerebellar neurons [50], Ishida et al. [51] differentiated Purkinje cells from iPSCs derived from hetero- and homozygous SCA6 patients [51]. They found that SCA6-derived Purkinje cells exhibit decreased expression of α1ACT and its target molecules, TAF1 and BTG1. They further constructed a disease model in which SCA6 patient-derived Purkinje cells specifically degenerate by depletion of the thyroid hormone triiodothyronine (T3), which is necessary in late stages of maturation. Bavassano et al. [107] differentiated SCA6 patient-derived iPSCs into neurons expressing Cav2.1 and α1ACT, using the same differentiation and stress model as for the SCA3 [118]. The glutamate loading decreased the viability of SCA6 neurons, pointing toward a common pathway of stress response in PolyQ SCAs. In addition, SCA6 neurons showed differences in the expression of several genes previously reported to depend on the transcriptional regulation by the α1ACT, and showed no differences in the electric response of the Cav2.1 channel. Recent high-throughput investigations in the mouse and human cerebellum revealed complex functions of α1ACT [26] and further studies are expected to clarify the role of the mutated α1ACT in cerebellar neurons, especially in Purkinje cells.
For SCA7, in which cerebellar and retinal cells are degenerated [151], Luo et al. [123] reported the generation of iPSCs and neurons from a SCA7 patient, but did not characterize the neuronal phenotype and the disease phenotype. Ward et al. [124] generated SCA7 patient-derived iPSCs and their isogenic lines transduced with either normal or expanded ATXN7. They reported that SCA7 iPSC-derived neural progenitors exhibit altered metabolism and mitochondrial dysfunction.
SCA36 and SCA42 are non PolyQ autosomal dominant diseases, affecting the cerebellar neurons and other neurons. Matsuzono et al. [126] generated motor neurons from the patient-derived iPSCs and recapitulated an increase in RNA foci-positive cells that can be markedly suppressed by treatment of antisense oligonucleotide. SCA42 is caused by a mutation in CACNA1G, which encodes T-type voltage-dependent calcium channel Cav3.1 [127]. In addition to identifying the affected gene, [127] reported a model disease for which patient-derived iPSCs were differentiated into Purkinje cells. The SCA42-derived Purkinje cells would provide a useful tool for further phenotype analysis of the mutated CAV3.1, for which the investigation was till now limited to the HEK293 cell line.
For the FRDA, a pioneering work revealed that abnormal expansion of GAA repeats led to upregulation of the DNA mismatch repair protein MSH2 in FRDA patient-derived iPSCs [130]. They reported that the functional inhibition of MSH2 by shRNA suppresses the repeat expansion. They further reported an inhibitor of histone deacetylase HDACi 109 increased the expression of FXN gene and Frataxin protein, pointing to the involvement of histone H3 lysine 9 in FXN expression. Polak et al. [131] also focused on epigenetic modifications in FRDA-derived iPSCs and performed drug evaluations. They found that an inhibitor of lysine-specific demethylation enzyme 1 (called Parnate or Tranylcypromine), and the HDAC inhibitor sodium butyrate have transient effects on decreasing the repeats and increasing FXN gene expression. Bird et al. [132] also reported a decrease in Frataxin expression in neurons differentiated from FRDA iPSCs, but could not detect abnormality in mitochondrial functions. Hick et al. [133] reported decreased expression of FXN and Frataxin, a decrease in mitochondrial membrane potential and degeneration of mitochondria in FRDA IPSC-derived neurons. Eigentler et al. [128] showed a cell-specific decrease of frataxin in disease-vulnerable FRDA iPSC-derived peripheral neurons. Lai et al. [129] and Mazzara et al. [134] generated FRDA isogenic lines. Mazzara et al. [134] demonstrated that the entire intron 1 removal, and not solely the elongation, was necessary for the recovery of the FXN expression level in peripheral sensory neurons. Although several studies have provided insights into the pathogenesis of FRDA in cardiomyocytes and peripheral neurons, additional work is required to elucidate the role of Frataxin in other affected cell types, such as the neurons of the DCN.
For the A-T is caused by several mutations in the ATM gene [152], Nayler et al. [135] differentiated A-T patient-derived iPSCs into cerebellar neurons and performed RNA sequencing analysis with them. Remarkably, they found that the generated neurons acquired properties of the cerebellum at GW 22 and exhibited disrupted gene regulatory networks related to synaptic vesicle dynamics and oxidative stress.
5. Strategies for optimizing the neuronal models of cerebellar ataxias
Of particular interest in future research in the cerebellar ataxias is the comparison between affected and unaffected neuronal types, in order to identify particular characteristics that render specific neuronal populations vulnerable to a genetic insult which is ubiquitously presented. One of the most crucial needs is to establish a reliable and consistent disease phenotype in a relevant cell population, and those cell types to be generated in relatively large quantities in vitro [153].
Differentiation into specific and mature neurons that are the disease targets, such as Purkinje cells for several SCAs, or solely DCN neurons for some ataxias, or both of them for the most of SCAs (Table 2), will enable the construction of more reliable disease models [154]. However, the suitability of iPSC-derived neurons for modeling late-onset conditions remains controversial, particularly given the immature, fetal-like phenotypes of the neurons generated from these cells.
Remarkably, in contrast to the immature morphology observed for human PSC-derived Purkinje cells, a recent bioinformatics analysis of their gene expression and developing showed that they most closely resembled late juvenile p21 mouse expression mouse Purkinje cells, when most of the cerebellar disease phenotypes in several animal models start to manifest. This finding suggests that the Purkinje cells are among the most mature human PSC-derived central neurons analyzed to date. This approach also underscores the utility of transcriptomic analysis for analyzing the maturation of human PSC-derived neurons and validates the use of hPSC-neurons for modeling cerebellar ataxias.
Still, it is possible that the disease phenotypes of adult-onset conditions, as the most of genetic SCAs are, may never be fully recapitulated under 2D cell culture conditions, even with directed protocols and optimized maturation. Generation of 3D cerebellar-like tissues as the cerebellar organoids may allow to increasing the neuronal maturation in vitro. The next generation or organoids or “assembloids”, which will allow the proper combination of different cell types, including vascularization, can offer a good perspective but also limitations by increased heterogeneity. The multiomics approaches at single-cell level can definitely contribute to understand and quantify this heterogeneity and in the same time decipher the cell-type related disease phenotype.
Another way to model the late-onset diseases is the addition of neural stressors, such as reactive oxygen species, pro-inflammatory factors, and toxins or forced aging, as schematically presented in Figure 5. These approaches were already used for modeling several SCAs or other neurologic diseases [153, 155, 156, 157]. However, in an ideal situation, these stressors should only exacerbate the disease phenotype, which can be evident in a good model solely by the expression of the mutation in the disease-relevant cells. Another approach is to genetically manipulate the system for forcing the aging, such as by overexpression of progerin in neural progenitors. By this approach, the disease phenotype is expected to manifest in vitro in earlier stages of neuronal maturation [155, 156] (reviewed in [158]).
On the other side, recent evidence from cell and animal models indicates that abnormalities in early Purkinje cell development may contribute to the pathogenesis of the ataxias Purkinje cell developmental abnormalities are clearly evident in a wide range of ataxic mouse mutants, including models of the degenerative SCAs [26]. The observed Purkinje cell developmental defects commonly include impaired dendritic arborization, resulting in synaptic deficits affecting CF and PF connections and ultimately altering Purkinje cell physiology. Similar impairments in Purkinje cell dendritogenesis and synapse formation have been described in mouse models of SCA5, and in cell and mouse models of SCA14, SCA1, SCA3 and SCA5. Given the increasing evidence for Purkinje cell developmental abnormalities in cerebellar ataxias, it seems likely that iPSC-derived models, which are capable of recapitulating early developmental events in vitro, will be invaluable in unraveling the pathogenic complexities of these conditions. It will be important to better understand the underlying—likely common—molecular mechanisms, by which mutations in distinct genes cause abnormal Purkinje cell development and function [159]. These could offer attractive future therapeutic targets to alleviate motor dysfunction in cerebellar ataxia.
Another limitation in the field of modeling cerebellar ataxias is that most of the studies implemeted the production of iPSCs from a few patients. On one hand, addressing to larger patient cohorts may allow to identifying more accurate phenotypes. On the other hand, for investigating the pathological function of a mutation, the ideal situation is to compare the cells bearing the mutation with control cells with an identical genetic background. The rapid development of CRISPR/Cas9-mediated genome editing is likely to result in significant advances in the field, allowing the correction of disease-causing mutations into iPSCs, which can then be used to create paired isogenic lines to produce better disease models in which far less patient-derived cell lines will be necessary [160]. This was already performed even for the ‘difficult to correct’ elongations, like in SCA3, SCA7, it is expected in the near future to constitute ‘the norm’ for all iPSC-derived disease models.
The establishment of efficient, reproducible cellular models of cerebellar dysfunction and degeneration will be important not only in elucidating the molecular basis of these diseases, but also in the development of effective therapies. Establishment of special cell cultures, such as Purkinje cells from patients with cerebellar ataxia, provides opportunities to screen for drugs that may correct the observed disease phenotypes. These cell cultures can be combined with stressors capable of eliciting phenotypes in late-onset conditions and genotypic modifiers of disease progression and drug response. In addition, these cerebellar cell cultures may be used for toxicity screens, to assess the effects of novel compounds on relevant cell types, or for differentiation screens, to identify compounds capable of enhancing self-renewal, maturation or survival of specific cerebellar cells (Figure 5).
6. Final remarks
Recent technologies for producing iPSCs from patients combined with the differentiation of PSCs into neural cells and the self-organizing 3D neural tissues have provided a new way to experimentally investigate the developmental and disease mechanisms of the human brain. While several challenges have hindered the generation of cerebellar neurons in vitro, starting from human PSCs, some important steps have been made. These protocols, combined with the patient-derived iPSCs, have been further applied for the investigation of several cerebellar diseases. In addition to the “classical” protocols aimed to generate specific types of neurons in two-dimensional (2D) cell cultures, recent progress has been made in culturing cells in three-dimensional (3D) structures, which may better reproduce the tissue organization and complexity in vivo, such as the PSC-derived brain organoids. Despite promising results, a number of issues remain to be addressed before the iPSC-based models to be widely adopted. Generation of the disease-relevant cerebellar cells and tissue in vitro remains a challenge, requiring a precise understanding of the complex molecular events during the development of each neuronal subtype, and an accurate set of markers by which to identify and characterize the generated cells. The 3D brain models in general and the 3D cerebellar models in particular still wait for improvements, including a better cellular characterization and an increased reliability, in order to contribute to better disease models.
However, human PSC-based models offer distinct advantages for the study of cerebellar ataxias. Cerebellar neuronal models are likely to provide valuable insights into the selective vulnerability of distinct neuronal subtypes, particularly the Purkinje cells. More directed and/or complex approaches will allow for the generation of accurate, disease-relevant models for the study of the molecular mechanisms underlying cerebellar ataxias, and the development of the long-awaited therapies.
Acknowledgments
This work was supported by Austrian Science Fund (FWF), Project P26886-B19, Austria.
\n',keywords:"cerebellar ataxias, iPSC-derived cellular models, cerebellar neurogenesis, Purkinje cells, cerebellar organoids",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75930.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75930.xml",downloadPdfUrl:"/chapter/pdf-download/75930",previewPdfUrl:"/chapter/pdf-preview/75930",totalDownloads:213,totalViews:0,totalCrossrefCites:0,dateSubmitted:"July 30th 2020",dateReviewed:"February 16th 2021",datePrePublished:"April 28th 2021",datePublished:null,dateFinished:"March 25th 2021",readingETA:"0",abstract:"The most affected cell types in cerebellar ataxias are the cerebellar neurons, which are not readily accessible for cellular and molecular investigation. Pluripotent stem cell (PSC) technology has emerged as an important tool for generating diverse types of neurons, which are used in order to better understand the human nervous system development and pathologies. In this chapter, the strategies for the differentiation of human PSCs toward cerebellar neurons are overviewed, followed by an outlook of their further optimization and diversification by implementing the knowledge from cerebellar development and new cell culture approaches. The optimization stategies are based on the recent progress made in defining the cell populations in mature and developing mouse and human cerebellum. The cellular phenotypes and organization in mouse and human cerebellum are briefly presented, followed by an overview of our current knowledge about their development, which includes pattering, proliferation, neurogenesis, gliogenesis, migration, connectivity and maturation. To date, however, relatively few studies have used induced PSCs (iPSCs) to model cerebellar ataxias and even fewer have looked directly to cerebellar neurons. The reported iPSC-derived in vitro models for cerebellar ataxias are reviewed, followed by an outlook of how to improve these models by generating and exporing the cerebellar neurons.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75930",risUrl:"/chapter/ris/75930",signatures:"Roxana Deleanu",book:{id:"9625",type:"book",title:"Spinocerebellar Ataxia - Concepts, Particularities and Generalities",subtitle:null,fullTitle:"Spinocerebellar Ataxia - Concepts, Particularities and Generalities",slug:null,publishedDate:null,bookSignature:"Dr. Patricia Bozzetto Ambrosi",coverURL:"https://cdn.intechopen.com/books/images_new/9625.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-83880-837-2",printIsbn:"978-1-83880-836-5",pdfIsbn:"978-1-83880-967-6",isAvailableForWebshopOrdering:!0,editors:[{id:"221787",title:"Dr.",name:"Patricia",middleName:null,surname:"Bozzetto Ambrosi",slug:"patricia-bozzetto-ambrosi",fullName:"Patricia Bozzetto Ambrosi"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"62127",title:"Dr.",name:"Roxana",middleName:null,surname:"Nat",fullName:"Roxana Nat",slug:"roxana-nat",email:"Irina-Roxana.Nat@i-med.ac.at",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Differentiation of pluripotent stem cells toward cerebellar neurons",level:"1"},{id:"sec_3",title:"3. Strategies for the optimization of the human PSC-derived cerebellar cultures",level:"1"},{id:"sec_3_2",title:"3.1 Patterning and specification of the cerebellar progenitor cells",level:"2"},{id:"sec_4_2",title:"3.2 Coordinated formation of the cerebellar circuits",level:"2"},{id:"sec_5_2",title:"3.3 From development of the cerebellum to the optimization of the human PSC differentiation protocols",level:"2"},{id:"sec_7",title:"4. iPSC-derived models for cerebellar ataxias",level:"1"},{id:"sec_8",title:"5. Strategies for optimizing the neuronal models of cerebellar ataxias",level:"1"},{id:"sec_9",title:"6. Final remarks",level:"1"},{id:"sec_10",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Nat, R. and Eigentler, A., (2017). 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PMID: 16713569.'},{id:"B155",body:'Cohen-Carmon D, Sorek M, Lerner V, Divya MS, Nissim-Rafinia M, Yarom Y, Meshorer E. Progerin-Induced Transcriptional Changes in Huntington’s Disease Human Pluripotent Stem Cell-Derived Neurons. Mol Neurobiol. 2020 Mar;57(3):1768-1777. PMID: 31939145.'},{id:"B156",body:'Miller JD, Ganat YM, Kishinevsky S, Bowman RL, Liu B, Tu EY, Mandal PK, Vera E, Shim JW, Kriks S, Taldone T, Fusaki N, Tomishima MJ, Krainc D, Milner TA, Rossi DJ, Studer L. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell. 2013 Dec 5;13(6):691-705. doi: 10.1016/j.stem.2013.11.006. PMID: 24315443; PMCID: PMC4153390.'},{id:"B157",body:'Tamada A, Watanabe S, Muguruma K. Investigating developmental and disease mechanisms of the cerebellum with pluripotent stem cells. Mol Cell Neurosci. 2020 Sep;107:103530. doi: 10.1016/j.mcn.2020.103530. Epub 2020 Jul 18. PMID: 32693017.'},{id:"B158",body:'Cornacchia D, Studer L. Back and forth in time: Directing age in iPSC-derived lineages. Brain Res. 2017a Feb 1;1656:14-26. doi: 10.1016/j.brainres.2015.11.013. Epub 2015 Nov 17. PMID: 26592774; PMCID: PMC4870156.'},{id:"B159",body:'Bettencourt C, Ryten M, Forabosco P, Schorge S, Hersheson J, Hardy J, Houlden H; United Kingdom Brain Expression Consortium. Insights from cerebellar transcriptomic analysis into the pathogenesis of ataxia. JAMA Neurol. 2014 Jul 1;71(7):831-9. doi: 10.1001/jamaneurol.2014.756. PMID: 24862029; PMCID: PMC4469030.'},{id:"B160",body:'Adli M. The CRISPR tool kit for genome editing and beyond. Nat Commun. 2018 May 15;9(1):1911. doi: 10.1038/s41467-018-04252-2. PMID: 29765029; PMCID: PMC5953931.'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Roxana Deleanu",address:"irina-roxana.deleanu@i-med.ac.at",affiliation:'
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Despite its highefficiency, widely acclaimed potentials, and limitations, the Low Salinity Water Flooding (LSWF), hybrid, and nanotechnology applications have gained vast interest with promising future to increase ultimate oil recovery, tackle operational challenges, reduce environmental damage, and allow the highest feasible recoveries with lower production costs. This synergistic combination has opened new routes for novel materials with fascinating properties. This book aims to provide an overview of EOR technology such as LSWF, hybrid, and nanotechnology applications in EOR processes.",editors:[{id:"120519",title:"Prof.",name:"Ariffin",surname:"Samsuri",slug:"ariffin-samsuri",fullName:"Ariffin Samsuri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",title:"Edited Volume"}},{id:"6532",type:"book",slug:"drilling",title:"Drilling",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6532.jpg",abstract:"With regard to depleted oil and gas resources, increasing world energy demands and volatile economic and political world scenarios, oil and gas industry players are working very hard to find ways to cut exploration and production costs to sustain and develop the industry to provide the world with cheap energy without harming the environment. Therefore, this book intends to provide readers with a comprehensive overview of the current state of the art in drilling, such as advanced drilling operations and techniques used by the industry, particularly in floating, underbalanced drilling, smart drilling fluid, intelligent drilling, drilling optimization, and future drilling technology and development.",editors:[{id:"120519",title:"Prof.",name:"Ariffin",surname:"Samsuri",slug:"ariffin-samsuri",fullName:"Ariffin Samsuri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",title:"Edited Volume"}}],chaptersAuthored:[{id:"30630",title:"The Needs for Carbon Dioxide Capture from Petroleum Industry: A Comparative Study in an Iranian Petrochemical Plant by Using Simulated Process Data",slug:"the-needs-for-carbon-dioxide-capture-from-petroleum-industry-a-comparative-study-in-an-iranian-petro",abstract:null,signatures:"Mansoor Zoveidavianpoor, Ariffin Samsuri, Seyed Reza Shadizadeh and Samir Purtjazyeri",authors:[{id:"92105",title:"Dr.",name:"Mansoor",surname:"Zoveidavianpoor",fullName:"Mansoor Zoveidavianpoor",slug:"mansoor-zoveidavianpoor",email:"mansoor353@yahoo.com"},{id:"120519",title:"Prof.",name:"Ariffin",surname:"Samsuri",fullName:"Ariffin Samsuri",slug:"ariffin-samsuri",email:"ariffin@petroleum.utm.my"},{id:"120520",title:"Prof.",name:"Seyed Reza",surname:"Shadizadeh",fullName:"Seyed Reza Shadizadeh",slug:"seyed-reza-shadizadeh",email:"Shadizadeh@put.ac.ir"},{id:"120521",title:"Dr.",name:"Samir",surname:"Purjazayeri",fullName:"Samir Purjazayeri",slug:"samir-purjazayeri",email:"S_purjazayeri@put.ac.ir"}],book:{id:"2117",title:"Greenhouse Gases",slug:"greenhouse-gases-capturing-utilization-and-reduction",productType:{id:"1",title:"Edited Volume"}}},{id:"38137",title:"Overview of Environmental Management by Drill Cutting Re-Injection Through Hydraulic Fracturing in Upstream Oil and Gas Industry",slug:"overview-of-environmental-management-by-drill-cutting-re-injection-through-hydraulic-fracturing-in-u",abstract:null,signatures:"Mansoor Zoveidavianpoor, Ariffin Samsuri and Seyed Reza Shadizadeh",authors:[{id:"92105",title:"Dr.",name:"Mansoor",surname:"Zoveidavianpoor",fullName:"Mansoor Zoveidavianpoor",slug:"mansoor-zoveidavianpoor",email:"mansoor353@yahoo.com"},{id:"120519",title:"Prof.",name:"Ariffin",surname:"Samsuri",fullName:"Ariffin Samsuri",slug:"ariffin-samsuri",email:"ariffin@petroleum.utm.my"},{id:"120520",title:"Prof.",name:"Seyed Reza",surname:"Shadizadeh",fullName:"Seyed Reza Shadizadeh",slug:"seyed-reza-shadizadeh",email:"Shadizadeh@put.ac.ir"}],book:{id:"2168",title:"Sustainable Development",slug:"sustainable-development-authoritative-and-leading-edge-content-for-environmental-management",productType:{id:"1",title:"Edited Volume"}}},{id:"61383",title:"Rate of Penetration Prediction Utilizing Hydromechanical Specific Energy",slug:"rate-of-penetration-prediction-utilizing-hydromechanical-specific-energy",abstract:"The prediction and the optimization of the rate of penetration (ROP), an important measure of drilling performance, have increasingly generated great interest. Several empirical techniques have been explored in the literature for the prediction and the optimization of ROP. In this study, four commonly used artificial intelligence (AI) algorithms are explored for the prediction of ROP based on the hydromechanical specific energy (HMSE) ROP model parameters. The AIs explored are the artificial neural network (ANN), extreme learning machine (ELM), support vector regression (SVR), and least-square support vector regression (LS-SVR). All the algorithms provided results with accuracy within acceptable range. The utilization of HMSE in selecting drilling variables for the prediction models provided an improved and consistent methodology of predicting ROP with drilling efficiency optimization objectives. This is valuable from an operational point of view, because it provides a reference point for measuring drilling efficiency and performance of the drilling process in terms of energy input and corresponding output in terms of ROP. 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(NPC-RT) with around 20 years of experience. She received her PhD degree in Chemical Engineering from Amirkabir University of Technology, Tehran, Iran. Her principal areas of interest and expertise include natural gas conversion and environmental researches, she is specifically focused on hydrogenation processes, carbon dioxide utilization and paraffin dehydrogenation. To date, she has published around 70 scientific papers in national and international journals, and presented more than 70 papers in national and international conferences. 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From 2005 to 2006, she did a doctoral internship in the School of Engineering of the University of Porto, Portugal. She lectured in the School of Chemical and Food Engineering of UFSC in 2009 and, in march 2010, she joined the faculty of the School of Chemical Engineering of the Federal University of Paraná, Brazil. She has research experience in treatment and recycling of solid and gaseous wastes and her main expertise is in advanced oxidation processes and gas separation.",institutionString:null,institution:{name:"Federal University of Paraná",institutionURL:null,country:{name:"Brazil"}}},{id:"91913",title:"Dr.",name:"Moses",surname:"Adebajo",slug:"moses-adebajo",fullName:"Moses Adebajo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Queensland University of Technology",institutionURL:null,country:{name:"Australia"}}},{id:"92105",title:"Dr.",name:"Mansoor",surname:"Zoveidavianpoor",slug:"mansoor-zoveidavianpoor",fullName:"Mansoor Zoveidavianpoor",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/92105/images/system/92105.jpg",biography:"Dr. Mansoor Zoveidavianpoor has over 24 years of experience, built upon his technical, operational, and management roles in the industry and academia. Mansoor holds a BSc degree in Geology, MSc, and Ph.D. degrees both in Petroleum Engineering. He was involved in different disciplines such as project management, geology, flow assurance, piping construction, artificial intelligence, environmental engineering, drilling and production engineering, He has lectured several courses at the University Technology Malaysia (UTM), Petroleum University of Technology (PUT), and Islamic Azad University (IAU). He is a member of the Society of Petroleum Engineers (SPE) and registered as a Chartered Petroleum Engineer at Energy Institute, and EIA subject specialist at DOE Malaysia. He has published more than 50 publications on International peer-reviewed Journals and conferences, has contributed to 5 textbooks, and served in many scientific committees. Currently, he is working as an Associate Professor at UTM and involved in several consultancies in petroleum engineering and energy transition. Mansoor is actively involved in multidisciplinary studies and currently, his main focus is on Energy Transition.",institutionString:"PETRONAS",institution:null},{id:"97967",title:"Dr.",name:"Ali",surname:"Kargari",slug:"ali-kargari",fullName:"Ali Kargari",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Amirkabir University of Technology",institutionURL:null,country:{name:"Iran"}}},{id:"99654",title:"Prof.",name:"Alírio",surname:"Rodrigues",slug:"alirio-rodrigues",fullName:"Alírio Rodrigues",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Porto",institutionURL:null,country:{name:"Portugal"}}},{id:"100023",title:"Prof.",name:"Ray",surname:"Frost",slug:"ray-frost",fullName:"Ray Frost",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Queensland University of Technology",institutionURL:null,country:{name:"Australia"}}},{id:"120520",title:"Prof.",name:"Seyed Reza",surname:"Shadizadeh",slug:"seyed-reza-shadizadeh",fullName:"Seyed Reza Shadizadeh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"120521",title:"Dr.",name:"Samir",surname:"Purjazayeri",slug:"samir-purjazayeri",fullName:"Samir Purjazayeri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"oai-pmh",title:"OAI-PMH",intro:'
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After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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A number of options are suggested for development of global water resource and food production.",book:{id:"7645",slug:"desalination-challenges-and-opportunities",title:"Desalination",fullTitle:"Desalination - Challenges and Opportunities"},signatures:"Sheikh Mohammad Fakhrul Islam and Zahurul Karim",authors:[{id:"288119",title:"Prof.",name:"S.M. Fakhrul",middleName:null,surname:"Islam",slug:"s.m.-fakhrul-islam",fullName:"S.M. Fakhrul Islam"},{id:"288121",title:"Prof.",name:"Zahurul",middleName:null,surname:"Karim",slug:"zahurul-karim",fullName:"Zahurul Karim"}]},{id:"60850",doi:"10.5772/intechopen.76624",title:"Wastewater Treatment Using Membrane Technology",slug:"wastewater-treatment-using-membrane-technology",totalDownloads:2961,totalCrossrefCites:14,totalDimensionsCites:29,abstract:"Water contamination by heavy metals, cyanides and dyes is increasing globally and needs to be addressed as this will lead to water scarcity as well as water quality. Different techniques have been used to clean and renew water for human consumption and agricultural purposes but they each have limitations. Among those techniques, membrane technology is promising to solve the issues. Nanotechnology present a great potential in wastewater treatment to improve treatment efficiency of wastewater treatment plants. In addition, nanotechnology supplement water supply through safe use of modern water sources. This chapter reviews recent development in membrane technology for wastewater treatment. Different types of membrane technologies, their properties, mechanisms advantages, limitations and promising solutions have been discussed.",book:{id:"6539",slug:"wastewater-and-water-quality",title:"Wastewater and Water Quality",fullTitle:"Wastewater and Water Quality"},signatures:"Azile Nqombolo, Anele Mpupa, Richard M. Moutloali and Philiswa\nN. Nomngongo",authors:[{id:"191669",title:"Dr.",name:"Philiswa",middleName:null,surname:"Nomngongo",slug:"philiswa-nomngongo",fullName:"Philiswa Nomngongo"}]},{id:"9113",doi:"10.5772/7588",title:"Photocatalytic Processes on the Oxidation of Organic Compounds in Water",slug:"photocatalytic-processes-on-the-oxidation-of-organic-compounds-in-water",totalDownloads:5773,totalCrossrefCites:3,totalDimensionsCites:24,abstract:null,book:{id:"3704",slug:"new-trends-in-technologies",title:"New Trends in Technologies",fullTitle:"New Trends in Technologies"},signatures:"C. J. Philippopoulos and M. D Nikolaki",authors:null},{id:"70242",doi:"10.5772/intechopen.90256",title:"Advancements in the Fenton Process for Wastewater Treatment",slug:"advancements-in-the-fenton-process-for-wastewater-treatment",totalDownloads:1873,totalCrossrefCites:9,totalDimensionsCites:21,abstract:"Fenton is considered to be one of the most effective advanced treatment processes in the removal of many hazardous organic pollutants from refractory/toxic wastewater. It has many advantages, but drawbacks are significant such as a strong acid environment, the cost of reagents consumption, and the large production of ferric sludge, which limits Fenton’s further application. The development of Fenton applications is mainly achieved by improving oxidation efficiency and reducing sludge production. This chapter presents a review on fundamentals and applications of conventional Fenton, leading advanced technologies in the Fenton process, and reuse methods of iron containing sludge to synthetic and real wastewaters are discussed. Finally, future trends and some guidelines for Fenton processes are given.",book:{id:"9415",slug:"advanced-oxidation-processes-applications-trends-and-prospects",title:"Advanced Oxidation Processes",fullTitle:"Advanced Oxidation Processes - Applications, Trends, and Prospects"},signatures:"Min Xu, Changyong Wu and Yuexi Zhou",authors:[{id:"307479",title:"Dr.",name:"Changyong",middleName:null,surname:"Wu",slug:"changyong-wu",fullName:"Changyong Wu"},{id:"307546",title:"Prof.",name:"Yuexi",middleName:null,surname:"Zhou",slug:"yuexi-zhou",fullName:"Yuexi Zhou"},{id:"311139",title:"Dr.",name:"Min",middleName:null,surname:"Xu",slug:"min-xu",fullName:"Min Xu"}]},{id:"67689",doi:"10.5772/intechopen.86952",title:"Membrane Distillation: Basics, Advances, and Applications",slug:"membrane-distillation-basics-advances-and-applications",totalDownloads:1444,totalCrossrefCites:9,totalDimensionsCites:20,abstract:"Membrane technology as an emerging separation process has become competitive with other separation techniques in recent decades. Among pressure-driven and isothermal membrane processes, membrane distillation (MD) as a thermally driven process has come out to put an end to hardships of such processes like distillation. MD process can be used in a wide variety of applications such as desalination and wastewater treatment. Generally, MD is a process which water is a main component of the feed solution and only water vapor can pass through a hydrophobic membrane pores. With four main configurations different from each other by their condensation procedure, the performance of MD process is limited due to the lack of appropriate module, membrane, and energy consumption rate. In recent years, many experiments have been carried out to find well-suited membrane type and module. Also, applying solar or waste heat as heat source and the capability of coupling with other processes like forward osmosis and osmotic distillation distinguish MD process from other membrane processes. This chapter addresses membrane characteristics, MD applications, transport mechanisms, and process challenges.",book:{id:"8915",slug:"advances-in-membrane-technologies",title:"Advances in Membrane Technologies",fullTitle:"Advances in Membrane Technologies"},signatures:"Mohammad Reza Shirzad Kebria and Ahmad Rahimpour",authors:[{id:"289042",title:"Associate Prof.",name:"Ahmad",middleName:null,surname:"Rahimpour",slug:"ahmad-rahimpour",fullName:"Ahmad Rahimpour"},{id:"289043",title:"Mr.",name:"Mohammad Reza",middleName:null,surname:"Shirzad Kebria",slug:"mohammad-reza-shirzad-kebria",fullName:"Mohammad Reza Shirzad Kebria"}]}],mostDownloadedChaptersLast30Days:[{id:"70242",title:"Advancements in the Fenton Process for Wastewater Treatment",slug:"advancements-in-the-fenton-process-for-wastewater-treatment",totalDownloads:1873,totalCrossrefCites:9,totalDimensionsCites:21,abstract:"Fenton is considered to be one of the most effective advanced treatment processes in the removal of many hazardous organic pollutants from refractory/toxic wastewater. It has many advantages, but drawbacks are significant such as a strong acid environment, the cost of reagents consumption, and the large production of ferric sludge, which limits Fenton’s further application. The development of Fenton applications is mainly achieved by improving oxidation efficiency and reducing sludge production. This chapter presents a review on fundamentals and applications of conventional Fenton, leading advanced technologies in the Fenton process, and reuse methods of iron containing sludge to synthetic and real wastewaters are discussed. Finally, future trends and some guidelines for Fenton processes are given.",book:{id:"9415",slug:"advanced-oxidation-processes-applications-trends-and-prospects",title:"Advanced Oxidation Processes",fullTitle:"Advanced Oxidation Processes - Applications, Trends, and Prospects"},signatures:"Min Xu, Changyong Wu and Yuexi Zhou",authors:[{id:"307479",title:"Dr.",name:"Changyong",middleName:null,surname:"Wu",slug:"changyong-wu",fullName:"Changyong Wu"},{id:"307546",title:"Prof.",name:"Yuexi",middleName:null,surname:"Zhou",slug:"yuexi-zhou",fullName:"Yuexi Zhou"},{id:"311139",title:"Dr.",name:"Min",middleName:null,surname:"Xu",slug:"min-xu",fullName:"Min Xu"}]},{id:"71660",title:"Applications of Chemical Kinetics in Heterogeneous Catalysis",slug:"applications-of-chemical-kinetics-in-heterogeneous-catalysis",totalDownloads:1104,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"Chemical kinetics is a key subdiscipline of physical chemistry that studies the reaction rate in every elemental step and corresponding catalytic mechanism. It mainly concludes molecular reaction dynamics, catalytic dynamics, elemental reaction dynamics, macrodynamics, and microdynamics. Such a research field has wide applications in heterogeneous catalysis. Based on the Arrhenius plot fitted by the catalytic conversions below 15% without the mass transfer effect and heat transfer effect, the apparent activation energy echoing with the intrinsically catalytic sites and the pre-exponential factor echoing with the relative number of active sites can be, respectively, derived from the slope and intercept of the Arrhenius plots, which can be used to compare the intrinsically catalytic activity of different catalysts and the relative amount of active sites. Reaction orders of both reactants and products are derived from the reaction rate equation and also fitted by the catalytic conversions below 15% without the mass transfer effect and heat transfer effect. According to the acquired reaction orders, the reaction mechanism can be proposed and even defined in some simple reactions. Therefore, investigations of chemical kinetics are of extreme importance and meaning in heterogeneous catalysis.",book:{id:"9415",slug:"advanced-oxidation-processes-applications-trends-and-prospects",title:"Advanced Oxidation Processes",fullTitle:"Advanced Oxidation Processes - Applications, Trends, and Prospects"},signatures:"Zhenhua Zhang, Li-Ping Fan and Yue-Juan Wang",authors:[{id:"312555",title:"Prof.",name:"Zhenhua",middleName:null,surname:"Zhang",slug:"zhenhua-zhang",fullName:"Zhenhua Zhang"},{id:"316868",title:"Ms.",name:"Li-Ping",middleName:null,surname:"Fan",slug:"li-ping-fan",fullName:"Li-Ping Fan"},{id:"316869",title:"Prof.",name:"Yue-Juan",middleName:null,surname:"Wang",slug:"yue-juan-wang",fullName:"Yue-Juan Wang"}]},{id:"77416",title:"Application of Water Quality Index for the Assessment of Water from Different Sources in Nigeria",slug:"application-of-water-quality-index-for-the-assessment-of-water-from-different-sources-in-nigeria",totalDownloads:516,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Water quality index (WQI) provides a single number that expresses the overall water quality, at a certain location and time, based on several water quality parameters. The objective of WQI is to turn complex water quality data into information that is understandable and usable by the public. A number of indices have been developed to summarize water quality data in an easily expressible and easily understood format. The WQI is basically a mathematical means of calculating a single value from multiple test results. This chapter discusses, in detail, the application of a water quality index for the assessment of water quality to different several water sources in Nigeria.",book:{id:"9921",slug:"promising-techniques-for-wastewater-treatment-and-water-quality-assessment",title:"Promising Techniques for Wastewater Treatment and Water Quality Assessment",fullTitle:"Promising Techniques for Wastewater Treatment and Water Quality Assessment"},signatures:"Ruth Olubukola Ajoke Adelagun, Emmanuel Edet Etim and Oko Emmanuel Godwin",authors:[{id:"256167",title:"Dr.",name:"Emmanuel",middleName:null,surname:"Edet Etim",slug:"emmanuel-edet-etim",fullName:"Emmanuel Edet Etim"},{id:"345734",title:"Mr.",name:"Oko",middleName:null,surname:"Emmanuel Godwin",slug:"oko-emmanuel-godwin",fullName:"Oko Emmanuel Godwin"},{id:"345735",title:"Dr.",name:"Ruth",middleName:null,surname:"Olubukola Ajoke Adelagun",slug:"ruth-olubukola-ajoke-adelagun",fullName:"Ruth Olubukola Ajoke Adelagun"}]},{id:"71348",title:"Water Treatment and Desalination",slug:"water-treatment-and-desalination",totalDownloads:1049,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Water covers a large area of the earth that reaches about three quarters of the surface of this planet, but we cannot say that all of this water is fresh or drinkable; according to many statistics, the percentage of fresh water reaches about 1% of the total water on earth. But with the great need for fresh water, whether for drinking or other purposes such as agriculture, the search for water treatment methods has become much larger. One of the most important of these methods that have been developed is desalination of seawater using desalination plants; therefore, we will address here the most important methods used in desalination and water treatment.",book:{id:"7645",slug:"desalination-challenges-and-opportunities",title:"Desalination",fullTitle:"Desalination - Challenges and Opportunities"},signatures:"Mona M. Amin Abdel-Fatah and Ghada Ahmed Al Bazedi",authors:[{id:"286268",title:"Associate Prof.",name:"Mona",middleName:null,surname:"Abdel-Fatah",slug:"mona-abdel-fatah",fullName:"Mona Abdel-Fatah"},{id:"295973",title:"Dr.",name:"Ghada",middleName:null,surname:"Al-Basedi",slug:"ghada-al-basedi",fullName:"Ghada Al-Basedi"}]},{id:"69228",title:"Advances in Passive Cooling Design: An Integrated Design Approach",slug:"advances-in-passive-cooling-design-an-integrated-design-approach",totalDownloads:2073,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"Incorporating passive cooling devices within building design requires analysis of device variables and actions to improve cooling performance, maximize efficiency, and integrate with building elements. Improving devices performance requires understanding the relation of devices to design stages, building elements, and working mechanism, and actions performed by devices to enhance cooling process and effectiveness. Therefore, designers could integrate passive devices as intrinsic design elements. The current research introduces SARS as an innovative classification of passive devices based on cooling actions that are performed by a device like storing, avoidance, removal or slowing (SARS). All actions, devices, and variables were discussed and analyzed to help integrate them within design stages: analysis, designing, and performance. Understanding actions will help maximize the performance of the devices, combine two or more devices together, and integrate the devices’ deign in design process. Combining more devices together to perform more than one function will move passive design to a new level to become as whole building design approach and to be a core design element.",book:{id:"8496",slug:"zero-and-net-zero-energy",title:"Zero and Net Zero Energy",fullTitle:"Zero and Net Zero Energy"},signatures:"Ahmed A.Y. Freewan",authors:[{id:"284866",title:"Dr.",name:"Ahmed A.Y.",middleName:null,surname:"Freewan",slug:"ahmed-a.y.-freewan",fullName:"Ahmed A.Y. Freewan"}]}],onlineFirstChaptersFilter:{topicId:"287",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
\r\n
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\r\n
\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
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\r\n\t
\r\n
\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
",coverUrl:"https://cdn.intechopen.com/series/covers/24.jpg",latestPublicationDate:"May 19th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"262440",title:"Prof.",name:"Usha",middleName:null,surname:"Iyer-Raniga",slug:"usha-iyer-raniga",fullName:"Usha Iyer-Raniga",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRYSXQA4/Profile_Picture_2022-02-28T13:55:36.jpeg",biography:"Usha Iyer-Raniga is a professor in the School of Property and Construction Management at RMIT University. Usha co-leads the One Planet Network’s Sustainable Buildings and Construction Programme (SBC), a United Nations 10 Year Framework of Programmes on Sustainable Consumption and Production (UN 10FYP SCP) aligned with Sustainable Development Goal 12. The work also directly impacts SDG 11 on Sustainable Cities and Communities. She completed her undergraduate degree as an architect before obtaining her Masters degree from Canada and her Doctorate in Australia. Usha has been a keynote speaker as well as an invited speaker at national and international conferences, seminars and workshops. Her teaching experience includes teaching in Asian countries. She has advised Austrade, APEC, national, state and local governments. She serves as a reviewer and a member of the scientific committee for national and international refereed journals and refereed conferences. She is on the editorial board for refereed journals and has worked on Special Issues. Usha has served and continues to serve on the Boards of several not-for-profit organisations and she has also served as panel judge for a number of awards including the Premiers Sustainability Award in Victoria and the International Green Gown Awards. Usha has published over 100 publications, including research and consulting reports. Her publications cover a wide range of scientific and technical research publications that include edited books, book chapters, refereed journals, refereed conference papers and reports for local, state and federal government clients. She has also produced podcasts for various organisations and participated in media interviews. She has received state, national and international funding worth over USD $25 million. Usha has been awarded the Quarterly Franklin Membership by London Journals Press (UK). Her biography has been included in the Marquis Who's Who in the World® 2018, 2016 (33rd Edition), along with approximately 55,000 of the most accomplished men and women from around the world, including luminaries as U.N. Secretary-General Ban Ki-moon. In 2017, Usha was awarded the Marquis Who’s Who Lifetime Achiever Award.",institutionString:null,institution:{name:"RMIT University",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:5,paginationItems:[{id:"91",title:"Sustainable Economy and Fair Society",coverUrl:"https://cdn.intechopen.com/series_topics/covers/91.jpg",isOpenForSubmission:!0,editor:{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo",profilePictureURL:"https://mts.intechopen.com/storage/users/181603/images/system/181603.jpg",biography:"Antonella Petrillo is a Professor at the Department of Engineering of the University of Naples “Parthenope”, Italy. She received her Ph.D. in Mechanical Engineering from the University of Cassino. Her research interests include multi-criteria decision analysis, industrial plant, logistics, manufacturing and safety. She serves as an Associate Editor for the International Journal of the Analytic Hierarchy Process. She is a member of AHP Academy and a member of several editorial boards. She has over 160 Scientific Publications in International Journals and Conferences and she is the author of 5 books on Innovation and Decision Making in Industrial Applications and Engineering.",institutionString:null,institution:{name:"Parthenope University of Naples",institutionURL:null,country:{name:"Italy"}}},editorTwo:null,editorThree:null},{id:"92",title:"Health and Wellbeing",coverUrl:"https://cdn.intechopen.com/series_topics/covers/92.jpg",isOpenForSubmission:!0,editor:{id:"348225",title:"Prof.",name:"Ann",middleName:null,surname:"Hemingway",slug:"ann-hemingway",fullName:"Ann Hemingway",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035LZFoQAO/Profile_Picture_2022-04-11T14:55:40.jpg",biography:"Professor Hemingway is a public health researcher, Bournemouth University, undertaking international and UK research focused on reducing inequalities in health outcomes for marginalised and excluded populations and more recently focused on equine assisted interventions.",institutionString:null,institution:{name:"Bournemouth University",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},{id:"93",title:"Inclusivity and Social Equity",coverUrl:"https://cdn.intechopen.com/series_topics/covers/93.jpg",isOpenForSubmission:!0,editor:{id:"210060",title:"Prof. Dr.",name:"Ebba",middleName:null,surname:"Ossiannilsson",slug:"ebba-ossiannilsson",fullName:"Ebba Ossiannilsson",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6LkBQAU/Profile_Picture_2022-02-28T13:31:48.png",biography:'Professor Dr. Ebba Ossiannilsson is an independent researcher, expert, consultant, quality auditor and influencer in the fields of open, flexible online and distance learning (OFDL) and the "new normal". Her focus is on quality, innovation, leadership, and personalised learning. She works primarily at the strategic and policy levels, both nationally and internationally, and with key international organisations. She is committed to promoting and improving OFDL in the context of SDG4 and the future of education. Ossiannilsson has more than 20 years of experience in her current field, but more than 40 years in the education sector. She works as a reviewer and expert for the European Commission and collaborates with the Joint Research Centre for Quality in Open Education. Ossiannilsson also collaborates with ITCILO and ICoBC (International Council on Badges and Credentials). She is a member of the ICDE Board of Directors and has previously served on the boards of EDEN and EUCEN. Ossiannilsson is a quality expert and reviewer for ICDE, EDEN and the EADTU. She chairs the ICDE OER Advocacy Committee and is a member of the ICDE Quality Network. She is regularly invited as a keynote speaker at conferences. She is a guest editor for several special issues and a member of the editorial board of several scientific journals. She has published more than 200 articles and is currently working on book projects in the field of OFDL. Ossiannilsson is a visiting professor at several international universities and was recently appointed Professor and Research Fellow at Victoria University of Wellington, NZ. Ossiannilsson has been awarded the following fellowships: EDEN Fellows, EDEN Council of Fellows, and Open Education Europe. She is a ICDE OER Ambassador, Open Education Europe Ambassador, GIZ Ambassador for Quality in Digital Learning, and part of the Globe-Community of Digital Learning and Champion of SPARC Europe. On a national level, she is a quality developer at the Swedish Institute for Standards (SIS) and for ISO. She is a member of the Digital Skills and Jobs Coalition Sweden and Vice President of the Swedish Association for Distance Education. She is currently working on a government initiative on quality in distance education at the National Council for Higher Education. She holds a Ph.D. from the University of Oulu, Finland.',institutionString:"Swedish Association for Distance Education, Sweden",institution:null},editorTwo:null,editorThree:null},{id:"94",title:"Climate Change and Environmental Sustainability",coverUrl:"https://cdn.intechopen.com/series_topics/covers/94.jpg",isOpenForSubmission:!1,editor:null,editorTwo:null,editorThree:null},{id:"95",title:"Urban Planning and Environmental Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/95.jpg",isOpenForSubmission:!0,editor:{id:"181079",title:"Dr.",name:"Christoph",middleName:null,surname:"Lüthi",slug:"christoph-luthi",fullName:"Christoph Lüthi",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRHSqQAO/Profile_Picture_2022-04-12T15:51:33.png",biography:"Dr. Christoph Lüthi is an urban infrastructure planner with over 25 years of experience in planning and design of urban infrastructure in middle and low-income countries. 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