\r\n\tThis volume presents the multifaceted aspects and should allow readers at all levels an entry into the exiting world of Chlamydomonas research.
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Blood vessel growth is a natural process driven by multiple stimuli of which hypoxia is one of the strongest inducing potent response until O2 pressure is normalized by the blood coming through de novo formed vasculature. However, a large group of diseases is caused by hypoxic or ischemic state of tissue. These include peripheral artery disease (PAD) and intermittent claudication (IC), coronary heart disease (CHD), myocardial infarction (MI) and ischemic stroke. Accompanied by endothelial dysfunction and age-related reduction of angiogenic response, they result in disabilities and mortality rate of 25–25% annually. Existing strategies for surgical bypass or endovascular interventions have limited efficacy as far as a cohort of non-option patients expands reaching 25–50% after certain extent of disease progression. Moreover, long-term prognosis after most interventions is negative as grafts undergo restenosis and vascular biocompatible prosthetics are yet to come for wide application. This drew attention of physicians and researchers to the concept of angiogenic therapy to stimulate body’s own resource and form new blood vessels to relieve ischemia. During recent decade the field of biomedicine known as therapeutic angiogenesis evolved rapidly using protein delivery, gene therapy, cell therapy and tissue engineering for induction of vessel growth and overview of its\x3c!-- Please define the abbreviation “AGENT, RAVE, OPTIMIST, EuroOPTIMIST, TAMARIS, STAT, TRAFFIC, SDF-1α, TALISMAN-201” at its first mention.
Postnatal growth of blood vessels is mediated by three mechanisms: vasculogenesis, angiogenesis and arteriogenesis [1]. Vasculogenesis is de novo formation of vasculature from specific progenitor or stem cells; however, it is attributed to prenatal period and after birth its role is unclear [2] and major extent of blood vessel formation involves two other mechanisms focusing our attention on them. Molecular and cellular basics underlying these processes became the cornerstones of therapeutic angiogenesis and become the source of novel objects for applied researchers and translational medicine.
\nAngiogenesis is the formation of a blood vessel de novo, yet in contrast to vasculogenesis, it relies on migration, proliferation and sprouting of existing endothelial cells (EC) comprising capillaries. The latter are small (8–15 μm) vessels lacking tunica media responsible for majority of tissue blood supply and O2/CO2 exchange [3]. Reduction of tissue O2 induces angiogenesis response in health (intense exercise, tissue growth, etc.) and in disease: in the case of interrupted or declining supply due to atherosclerotic lesions or anemia [4]. Under normal condition, capillaries are stabilized by autocrine and paracrine stimuli (Notch1 axis, angiopoietins, thrombospondin, angiostatin, transforming growth factor (TGF)-β, etc.) that balance influence of pro-angiogenic cytokines within blood vessels’ vicinity (vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGFs), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF)). Hypoxia dislodges this balance toward angiogenic events and this is mediated by O2-sensitive system existing in a variety of cells including EC themselves, smooth muscle cells (SMC), pericytes and fibroblasts. Cells respond to hypoxia via a system of hypoxia-induced factors (HIFs) [5]—a group of heterodimeric transcription regulators controlled by O2-sensitive prolyl hydroxylases. Briefly, stability of HIFs is increased drastically in hypoxic environment resulting in their binding to hypoxia-responsive elements within promoter regions of genes increasing their expression [6]. HIF-dependent genes include a vast array of cytokines stimulating EC proliferation, blood vessel sprouting and, thus, labeled “angiogenic growth factors” [7, 8]. The latter include soluble growth factors associated with EC proliferation and differentiation (acidic FGF (aFGF), basic FGF (bFGF), HGF, VEGFs) [9, 10] and cytokines bound to extracellular matrix (ECM) and released during its cleavage [11]. These changes induce EC proliferation and migration forming a vascular sprout guided by a “tip cell.” This cell follows a gradient of concentration and produces matrix metalloproteinases (MMPs) and urokinase (uPA) to cleave the ECM [12], releasing growth factors and basically tunneling ECM followed by “stalk cells” that form a new capillary [13]. After lumen formation occurs normalized blood supply switches off hypoxic stimuli, “tip cells” lose their phenotype and proteolytic potential [14] commencing microenvironment stabilization. Expression of tissue metalloproteinase inhibitors and Dll4-Notch1 axis [15] induction in EC is followed by reestablishment of a balanced state between pro- and antiangiogenic molecules in the tissue leaving a new capillary-sized blood vessel [16]. However, it should be mentioned that this sequence of events never occurs as a perfectly tuned mechanism. “Stub” branches are formed and must be removed, certain “tip cells” fail to form a sprout and maturation of vascular network includes dissociation of certain anastomoses [16], which overall describes angiogenesis as a dynamic process modulated by multiple stimuli [17]. Finally, under influence of stabilizing signals from surrounding EC, pericytes and stromal cells, the vascular bed returns to normal steady state.
Arteriogenesis is triggered by rise of shear stress after an occlusion and induces collateral vessel remodeling forming a bypass 20–100 μm in diameter with developed tunica media. Arteriogenesis may occur gradually (e.g., in increasing stenosis of a large-caliber artery) or can be triggered by a rapidly developed occlusion with both situations are to result in effective blood flow delivery “around an obstacle” to distal portions of the limb or organ [18]. Certain studies show that collateral remodeling can be reversible till certain point of this process in case shear stress drops to normal after thrombolysis or surgical thrombectomy [19]. Effective arteriogenesis may bypass up to 30–40% of basal blood flow in critical stenosis and thrombosis, which is sufficient for tissue survival. However, its efficacy is drastically reduced in disease and with aging [20]. Smoking-related hypercoagulation, hypertension and diabetes also limit arteriogenic response resulting in critical level of ischemia and tissue loss [21].
\nAfter pressure rise in collaterals above the site of thrombosis, shear stress induces EC membrane deformation and flow-sensitive ion channels activate downstream MAP-kinase (ERK1/2, Rho, etc.) phosphorylation and expression of, growth factors, adhesion molecules and chemokines (interleukin-8, macrophage chemoattractant proteins, etc.) [20]. Eventually leukocytes begin to “roll” on EC surface resembling inflammatory changes of vascular function and infiltrate the collateral’s wall [22]. Pivotal role in wall thickening is played by monocytes and their differentiated forms—macrophages and dendritic cells. Their function is not limited to ECM and basal lamina cleavage by MMP and uPA production to destabilize the collateral and make it “flexible” [23], but they seem to profoundly change the properties of the blood vessel by induction of SMC proliferation and hypertrophy [24]. Under these influences, media thickness may increase 3- to 4-fold and collateral vessel’s volume can enlarge up to 20-fold [25]. Moreover, monocytes produce a wide spectrum of angiogenic and mitogenic cytokines, some of which have antiapoptotic properties required for tissue protection [26]. The role of monocytes and macrophages has been especially emphasized in cardiac arteriogenesis where immunosuppressive steroid hormones [27], anti-inflammatory therapies and even aspirin [28] have been shown to negatively impact the outcomes and collateral remodeling. Toxic depletion of monocytes by clodronate reduced arteriogenesis in cryo-injured myocardium and led to decreased ventricular function and higher mortality [29]. As collaterals increase shear stress stimulus is relieved and EC reduce production of chemokines and lose their “adhesive” phenotype. Macrophages limit production of proteolytic enzymes and start ECM reconstruction producing collagens, laminin and elastin and forming adventitial and medial portions of a new arterial vessel.
\nTypically, we mention “therapeutic angiogenesis” referring gene or cell therapy to relieve ischemia. Nevertheless, one may see that angiogenesis and arteriogenesis share common mediators—namely growth factors and enzymes, ECM components, EC activation, etc. Eventually, for adequate function therapeutic angiogenesis has to rebuild both—medium/large-caliber arteries providing influx of blood and capillary-sized vessels that deliver it to the cells.
After the discovery of proteins with angiogenic effects, the concept of their therapeutic application was introduced by the 1990s and a vast array of animal studies was published to demonstrate angiogenic efficacy of recombinant protein delivery. Going beyond the VEGF family, experimental works showed induction of angiogenesis by FGFs, HGF, PDGF and placental growth factor (PlGF) in small rodents and rabbits [30, 31]. Injection of these cytokines to ischemic tissue or blood vessels increased perfusion and vascular density. However, promise of this method was questioned as far as achievement of local pharmacological concentration by injection was extremely expensive (especially for human body mass) and half-life of most cytokines was too low to render potent effects [32]. Furthermore, little was known on pharmacokinetics of recombinant proteins delivered intravascularly and their potential involvement in tumor growth and chance of “washout” to systemic blood flow raised safety concerns.
\nIn 2000, the first clinical trials of recombinant human bFGF were initiated in PAD/IC patients after a pilot study showing safety and tolerance of intra-arterial delivery of bFGF solution. Unfortunately, it was halted prior to completion of protocol due to urinalysis data revealing proteinuria in bFGF-treated subjects and no positive changes of endpoints at the moment when the trial was put to a premature end [33]. The final attempt to achieve success in the field was the Therapeutic angiogenesis with recombinant fibroblast growth Factor-2 for intermittent claudication (TRAFFIC) randomized placebo-controlled trial in patients with PAD showing significant improvement in walking time and ankle-brachial index (ABI) in bFGF group. However, safety profile was compromised and yet no cardiac adverse effects or evidence for tumor formation was found in recurrent cases of proteinuria and signs of nephrotoxicity were an issue [34].
\nThese results were as disappointing as valuable for the field and suggested that gene therapy with its local sustained expression of desired protein is the best alternative possible [32]. Recently, no further attempts to implicate protein delivery for therapeutic angiogenesis were made in clinics and advantages of other methods are exploited to patients’ benefit.
Gene therapy relies on delivery of genetic information by introduction of nucleic acids to target cells/tissues using vector systems. This results in local expression and production of desired protein over a certain period depending on vector used and properties of tissue. First experiments indicating possibility of in vivo gene delivery using simple injection of a recombinant plasmid DNA (pDNA) opened the gate for hundreds of studies published within the last two decades [35].
\nAs far as the “cornerstone” of gene therapy is the vector system, a brief overview of existing options is required. General concept in the field is that all vectors can be divided into “viral” and “nonviral” subgroups covering nearly any possible way of genetic material delivery. Among nonviral vectors, pDNA is the most widely used due to its long-studied safety profile, ease of production and low immunogenicity allowing repetitive administration [31, 36]. Moreover, plasmids are feasible for combined delivery of several growth factors by mixing them in a formulation or generating a multicistronic vector. However, low transfection efficacy (0.5–2.0% in various tissues) in large mammals including human is an efficacy-limiting issue for pDNA [37]. Viral delivery systems comprise a broad spectrum of recombinant or chimeric viruses of different capacity having a great potential. The latter is due to high transduction efficacy and long expression period accompanied by tissue tropism in certain viruses. However, disadvantages are safety issues: immune reactions and risk of carcinogenesis due to integration to host genome. The most widely spread vectors include\x3c!-- Please check the following sentence "The most widely spread include…" for clarity.
Period of growth factor-based gene delivery dates back to the seminal study by Dr. J. Isner [43] who used injection of pDNA encoding VEGF-A 165 (VEGF165) isoform to succeed in treatment of a non-option patient with critical limb ischemia. “First in-human” data were supported by Baumgartner et al. who found increased collateral formation after intramuscular delivery of VEGF165 and EC proliferation in amputation material providing proof of mechanism [44]. Later a number of vectors using VEGF-A and its isoforms were evaluated in experimental and clinical trials making it the most intensively studied object in therapeutic angiogenesis.
\nAmong numerous clinical examples, one may highlight the first “head-to-head” comparison of adenovirus with VEGF165 (Ad-VEGF165) and liposome-packed pDNA-VEGF165 in PAD patients undergoing angioplasty. The trial showed low clinical efficacy of both approaches—Rutherford severity class stayed comparable to control group yet vascular density was increased after treatment [45]. This and other studies using catheter delivery hinted that this method lacks site specificity and intramuscular injection technique was generally adopted. However, initial Groningen double-blind placebo-controlled trial intramuscular injection of pDNA-VEGF165 in PAD patients with diabetes mellitus failed the primary endpoint (amputation rate), yet improvements in ulcer healing, TcO2 and ABI were observed [46].
\nLater, Regional angiogenesis with VEGF (RAVE) trial was the first double-blind placebo-controlled trial of VEGF-A 121 isoform (VEGF121). This cytokine is considered to have better solubility than VEGF165 isoform as it lacks a heparin-binding domain [47]. Key feature of this study was an attempt to perform dose optimization of Ad-VEGF121 dividing 105 patients with PAD/IC into three subgroups that received a single session of 20 intramuscular injections of AdVEGF165 delivering low dose (4 × 109 particles), high dose (4 × 1010 particles), or placebo. Final assessment after 12 weeks revealed no significant differences in endpoints between control and treatment subgroups, yet dose-dependent increase of edema adverse effect was observed. Indeed, since first studies delivery of VEGF-A isoforms was haunted by evidence of edema formation due to its influence on endothelial permeability [48] with certain authors claiming this was a putative reason for low efficacy of therapy [49].
\nTrials in MI patients were initiated as early as in 1998 using a pDNA-VEGF165 showing good safety profile and no positive changes [50]. It was followed by Kuopio Angiogenesis Trial [51] using a comparative design with Ad-VEGF165 or pDNA-VEGF165 delivery by intramyocardial injection during transcutaneous angioplasty. In this trial, no differences between control and treatment groups were found, yet at 6 months after injection of Ad-VEGF165, myocardium perfusion was higher than pDNA-VEGF165, which was attributed to its high transduction efficacy. EuroInject One trial gave similar results showing no significant improvement of myocardial perfusion after injection of pDNA-VEGF165, yet local contractility was higher than control [52].
\nTrials using delivery of HGF were initiated and conducted by Dr. Morishita’s group aiming to treat PAD by intramuscular injection of pDNA-HGF. Encouraging results in animal models [31, 53] promoted clinical translation and after safety assessment a Phase II trial was initiated comparing single and repeated dose of pDNA-HGF in favor of multiple injections: only this dosing regimen showed improvement of TcO2 compared to control [54]. Further results in a placebo-controlled I/IIa phase trial showed good safety with no traces of secreted HGF in peripheral blood and repeated injection of 8 mg pDNA-HGF showed significant improvements of secondary endpoints (ulcer size, ABI and pain reduction) [55]. Similar results were obtained in a placebo-controlled trial in PAD patients where by the end of week 12, 70% decrease of ulcer size was observed [56]. Further attempts to increase efficacy included the use of a bicistronic plasmid encoding two forms of HGF named dHGF and cHGF. They were evaluated in animal models showing better perfusion after expression of dHGF + cHGF than each one alone [57]. Clinical trial of this approach in PAD patients showed that multifocal intramuscular injections of 4–16 mg of pDNA-dHGF/cHGF resulted in improvement within 3 months independently of dose: rest and walking pains reduced and a trend toward ulcer healing and increase of TcO2 was observed [58].
\nOverall, we may expect HGF-based drugs to become the first widely marketed for PAD—in Japan it has been registered under “Collategene” name and now undergoes stage III clinical trial in PAD cohort. Furthermore, despite HGF has never been tested for MI treatment in clinical settings, preclinical assessments indicate that it may be effective as it has antifibrotic and angiogenic mode of action that can be a good option for this disease or subsequent ventricular failure due to tissue scarring [53, 59].
\nFibroblast growth factor has been the first used in protein delivery and gene therapy studies were to follow as soon as it gained attention. Therapeutic angiogenesis leg ischemia study for the management of arteriopathy and non-healing ulcer (TALISMAN-201) have evaluated pDNA-FGF-1 in no-option PAD patients [60] and showed improvements as decreased amputation rate within 1 year after treatment [61] and its prospective part showed reduced general mortality in treated subjects [62]. However, phase III placebo-controlled “TAMARIS” (n = 525) trial drew disappointing results and all primary endpoints including amputation events failed to improve after treatment by pDNA-FGF-1 [62, 63]. Similar results obtained in OPTIMIST and EuroOPTIMIST trials indicated safety and lack of efficacy after treatment and lead to wrapping up of this prospective drug testing. Nevertheless, in a follow-up stage, important safety data showing no increased cancer, stroke, or MI in FGF-treated patients was obtained and positively impacted new proceedings in the field [64].
\nIn MI patients, FGF-4 was delivered using an intracoronary injection of an adenovirus with this gene (Ad-FGF-4) in an Angiogenic gene therapy (AGENT) trial. Result evaluation showed that the only subgroup with reduced size of ischemic myocardium after treatment was female patients when compared to male subgroup. The authors speculated that it may be attributed to higher extent of microcirculatory disorders in females [65, 66] accompanied by fewer critical stenosis typical in men [67]. As far as FGF-4 is known to positively influence endothelial function, this might have been the mechanism for observed changes in the trial. Among other therapeutic factors used for stimulation of angiogenesis, HIF-1α and development endothelial locus-1 (DEL) are both worth a mention as far as they made it to the bedside in recent years using adenovirus or pDNA vectors. However, trials showed minimal improvement in PAD patients and further evaluations were ceased up to date [68, 69].
\nOverall despite failure to show expected efficacy in clinic, gene therapy is safe and well tolerated by patients showing little evidence although long-term evaluations are yet to be completed. Key obstacle in pDNA-mediated gene therapy relates to transfection efficacy and thus protein production levels after administration [70]. Viral vectors show some promise in solving the problem, yet optimization of dosage regimen, delivery routes and administration protocols also provide a field for further development.
\nFrom the point of translational potential, pDNA-based gene therapy has the best safety profile and the best results are definitely yet to come in the following years yet points for improvement are obvious. Efficacy improvement in gene therapy can be achieved by combined approaches basing on the point that angiogenesis is a dynamic process controlled by numerous cytokines, each playing its party in initiation/cessation of different stages. This puts the basis for combined gene therapy to treat ischemia with higher efficacy and it has been supported by experimental findings using VEGF165 combined with another pro-angiogenic growth factor: bFGF [71], PDGF [72], angiopoietin-1 [73], or Stromal cell-derived factor-1α (SDF-1α) [74]. Our previous experience in mouse hind limb ischemia model showed that combination of VEGF165 and uPA [75] or HGF [76] induced angiogenic response more effectively than each factor alone or allowed to reduce pDNA dose for combined delivery [75]. A crucial transcription factor in angiogenesis, HIF-1α, was also used for combined gene therapy with VEGF165 showing good results in animal model [77] as well as bFGF + heme oxygenase-1 (HO-1) [78]. Regarding the latter, it is known that HO-1 is an important regulator of endothelial function with protective function. Its expression is known to induce angiogenesis in ischemic tissues and blockade or knockout reduces EC proliferation and motility and thus capillary growth [79].
\nTriple combined gene therapy has not been evaluated for angiogenesis, yet a study was published where controlled release scaffolds containing a mix of VEGF165, HGF and angiopoietin-1 or their double combinations were evaluated for enhancing efficacy of endothelial progenitor cell (EPC) therapy. Triple combinations resulted in significantly higher SMC counts indicating more efficient vessel stabilization due to angiopoietin-1 effects on perivascular cell chemotaxis [80].
\nAuthors claimed that the use of VEGF165 + another cytokine typically leads to decreased edema and vascular permeability: this has been shown for a well-known stabilizing cytokines—angiopoietin-1 [73] and HGF [81]. Thus, another rationale for combined therapy is decrease of certain “side effects” observed in “monotherapy” by VEGF as a key player in gene therapy. The latter point is not limited to reduction of adverse reactions, but also arises from a large spectrum of pleiotropic effects of cytokines. For example, VEGF may act as a pro-inflammatory cytokine by induction of nuclear factor κ-B, while HGF [82] or angiopoietin-1 shows antagonistic effects leading to reduction of VEGF-driven cell adhesion and inflammation [83]. Indeed, this has been confirmed in a number of in vitro tests and skin inflammation model indicating that these properties may be utilized for development of next-generation gene therapy drugs for angiogenesis exploiting pleiotropy of cytokines besides their main angiogenic effect. Another approach is delivery of growth factors in two sessions apart in time: for example, pre-treatment by angiopoietin-1 pDNA resulted in better angiogenic response after subsequent pDNA-VEGF165 injection in mouse hind limb ischemia model hinting time of administration as an important factor for efficacy [84].
Cell therapy is a promising tool for regenerative medicine and therapeutic angiogenesis using progenitor or stem cells’ ability to self-renew and mediate tissue repair. For potential use of cell therapy for vascular repair, one of the most intriguing findings was the discovery of endothelial progenitor cells (EPC) in circulating blood which hinted involvement of postnatal vasculogenesis in perfusion restoration [85]. However, further works sparkled controversy about EPC phenotype, origin [86], role in recovery from disease and even existence. Report by Prokopi et al. [87] claimed that EPC can be false-detected as endothelium-like (CD31/vWF+) monocytes in cultures due to phagocytosis of residual platelets rich with these protein markers.
\nClinical trials up to date focus on delivery of bone marrow (BM) cells for induction of angiogenesis. These studies evaluated effects of BM mesenchymal stem cells (BM-MSC) or mononuclear cells (BM-MNC) delivered by intramuscular or intravascular injection in PAD patients. Most studies supported efficacy and indicated improvement in evaluated endpoints: ABI, pain-free walking distance, TcO2, ulcer healing, or amputation-free period. However, some pivotal trials are to be mentioned in detail for better understanding of the field’s status.
\nFirst set of crucial data was obtained during “head-to-head” comparison of different cell types to identify the optimal cell source. In a double-blind randomized study, administration of BM-MSC to diabetic PAD patients with foot ulcerations showed efficacy superior to BM-MNC [88]. Subjects that received BM-MSC showed complete ulcer healing 4 weeks earlier than BM-MNC; perfusion assessment, pain-free walking time, ABI and angiography data also spoke in favor of BM-MSC as a more effective cellular angiogenic agent [88].
\nHowever, limitation of BM-based treatment is invasive procedure to obtain material and alternative approach was proposed using peripheral blood mononuclear cells (PB-MNC) mobilized by granulocyte colony-stimulating factor (G-CSF) pre-administration. Feasibility of this approach was obvious and a trial was initiated to confirm its efficacy compared to BM-MNC enrolling a total of 150 patients split in two groups. After 12 weeks of observation, PB-MNC patients showed significantly higher limb temperature, ABI and reduced rest pains than BM-MNC. Yet no difference was found in TcO2, ulcer healing rate and amputation frequency hinting that two methods showed comparable efficacy profile with a trend to PB-MNC application due to feasibility and endpoint improvements [89]. Interestingly, a trial of conventional therapy + G-CSF monotherapy was compared to BM cells and in these groups, improvements in ABI and TcO2 were comparable and significantly better than in conventional drug therapy control. This was an intriguing finding which showed that mobilization of endogenous mononuclear cells (MNC) was sufficient to replace BM grafting and injection [90].
\nAnother source of cells for therapeutic angiogenesis is adipose-derived mesenchymal stromal cells (AD-MSC). Despite sources of mesenchymal stem cells (MSC) are not limited to adipose tissue, these adult stromal cells can be isolated from samples obtained during lipoaspiration or surgery. Taken together with ease of expansion, well-established phenotype and abundance in healthy individuals, it makes AD-MSC an excellent object for autologous and allogeneic use for angiogenesis stimulation [91]. Published experimental studies show that AD-MSC use their paracrine potential for induction of angiogenesis and support of collateral remodeling [92]. This is referred as “bystander effect” to emphasize that AD-MSC render their effects by paracrine mechanism in contrast to previously existing opinion about their significant ability to differentiate into specific vascular cells and EC in particular [93].
\nThese cells have not been evaluated in PAD or MI clinical trials yet and considered to be a very attractive option to complement existing strategies. Certain factors limiting potency of AD-MSC exist including donors’ age [94], comorbidities and effects of ex vivo culture [95]. However, improvement can be achieved by manipulation of cells’ paracrine activity, e.g., by viral transduction to increase expression of cytokines forming an “alliance of gene and cell therapy” for higher efficacy [96]. This approach has become possible after development of effective viral gene delivery systems as far as pDNA transfection in primary human cultures was extremely low or at the level of toxicity exerted by transfection reagents [97]. Modification of cells intended for therapy use in performed ex vivo after sufficient amount of material is obtained in appropriate culture condition. Selection of a viral vector depends on safety precautions and vector capacity for genetic material; however, cDNA of most angiogenic cytokines “fit” into commonly used adenoviruses or adeno-associated virus (AAV).
\nThis method has been tested in animal models of ischemia using exogenous delivery of VEGF165 [98], insulin-like growth factor-1 [99], HO-1 [100], or other genes to different types of cells: AD-MSC, EC, BM-MSC, etc. In majority of reports, modification resulted in improvement of response after delivery to ischemic tissue. In our experience, administration of human VEGF165-expressing AD-MSC to ischemic limb of immunodeficient mice resulted in enhanced perfusion and vascular density superior to control cells. Furthermore, muscle necrosis was minimal in this group indicating enhanced blood supply and antiapoptotic effects of VEGF165 as mode of action [98].
\nApplication of modified stem cells for induction of angiogenesis may be limited in coming years unless safety of modification and full extent of its influence on biological properties of cells is understood. Ex vivo modified cells are widely used for treatment of oncology and hereditary disease where benefit for patient overwhelms existing risks [101]; however, for treatment of PAD and MI, additional measures of precaution will be required prior to active clinical trials. Nevertheless, recently a group led by Dr. J. Laird began a phase I trial to evaluate the use of VEGF-expressing MSC in patients with critical limb ischemia. The trial is now ongoing with expected completion in 2017 and preclinical data indicated good safety profile with long-term expression of VEGF in MSC after viral modification [102]. Recent progress in virus biology and gene engineering allowed development of safer vector systems with controlled expression, integration, or directed insertion to genomic “safe harbors” where they induce minimal to none disturbances [103]. Preclinical evaluation of these systems is expected to give more data on long-term impact of modification and facilitate translation.
Cell sheets (CS) were first introduced by Dr. Okano’s group and occupied a niche between 3D tissue engineering and 2D cell cultures used to obtain therapeutic cellular materials [104]. Briefly, CS is an attached mono- or multilayered xeno-free construct that consists of viable cells with ECM produced by these cells. Application of this method allowed to circumvent a crucial setback observed in a number of experimental works—poor survival of cells used for therapeutic interventions. One of main reasons for this is procedure of detachment by proteolytic enzymes leading to disruption of ECM (along with deposited cytokines) and loss of intercellular contacts resulting in anoikis and high prevalence of cell death aggravated by passage of cells through a catheter or needle causing mechanical damage. Loss of cells implanted to the tissue by injection in suspended form is estimated as 40–75% within the first 3 days [105], while CS limits this damage to minimum keeping the cells viable after delivery and enhancing their engraftment [106]. Furthermore, ECM proteins delivered as a part of the construct are known to have a beneficial impact on regeneration and do not have toxic or immunogenic features of chemical or xenogeneic scaffolds. Generation of CS is possible from MSC, fibroblasts, EC, skeletal myoblasts, induced pluripotent stem cells and cardiomyocytes derived from them, BM cells and cardiac progenitor cells [107]—literally, any adherent cell culture after it produces enough ECM to stand mechanical manipulation [108]. CS can be used to cover a significant surface making it a good technique for superficial lesions, cardiomyoplasty and ophthalmologic and microsurgical manipulations. Numerous clinical trials are being run in Japan these years to reveal their full potential in a wide array of disorders [109].
\nIn relation to angiogenesis, this technique was evaluated in MI models using CS from skeletal myoblasts, AD-MSC, or cardiac progenitor cells showing their ability to generate vascularized additional layer of tissue and facilitate vascular growth in underlying tissue [110, 111]. This resulted in improved ventricular function, limited MI size and fibrosis and favorable outcomes in experimental animals. Comparative study of CS vs. injection of suspended cells showed CS to be superior in terms of most functional and histological endpoints analyzed and using a bioluminescent method, the authors reported higher survival of transplanted rat neonatal cardiomyocytes after CS delivery compared to injection [112]. Recently, clinical application of CS from autologous skeletal myoblasts has begun to treat severe heart failure patients with left ventricular assist devices. Delivery of multilayered constructs resulted in ejection fraction increase sufficient to remove the device and postpone heart transplant as well showing good potential of this approach [113].
\nIn limb ischemia and diabetes, CS are generally considered to be a tool for ulcer treatment and indeed numerous clinical trials have been initiated within last years. However, our group has been extensively investigating application of CS as an angiogenic therapy in PAD. We have found that subcutaneous delivery of CS from AD-MSC to mice with limb ischemia resulted in robust angiogenic response and CS were superior to dispersed cells in terms of tissue perfusion and vessel density [114]. This piece of evidence provided basis for CS application in PAD indicating that their potential is not limited to cutaneous healing but that paracrine factors are capable to induce angiogenic response in ischemic muscle. Our data were supported almost at the same time in a study by Bak et al. who used mixed CS from SMC and EC for successful treatment of experimental limb ischemia in mice by subcutaneous delivery [115].
\nFurther improvement of CS potential is possible by application of ex vivo modification to express growth factors and discussed above. Our group’s experience with viral vectors expressing VEGF165 suggested robust increase of angiogenesis in MI and limb ischemia after delivery of sheets from AD-MSC expressing VEGF165 after viral transduction [114, 116]. Effect of these constructs was superior to control CS and we observed no changes in immune response to genetically modified sheets or cell proliferation/viability within them [114].
\nOverall, application of CS for therapeutic angiogenesis is a new field and its expansion is expected within next years. These constructs are feasible from a translational point of view as far as they do not contain xenogeneic, artificial, or cadaveric materials circumventing many ethical and safety problems in translation.
Overall, therapeutic angiogenesis has accumulated a “critical mass” of evidence and approaches that would allow its application in practice within the next 10–15 years expanding the capabilities of treatment. However, possibility to shift from initially used non-option or critical patients may lead to better results in clinical trials, especially in gene therapy, where numerous failures put the whole concept under question several years ago. Development of cell therapy was accompanied by a large framework of regulatory, legal, ethical and industrial work to ensure safety and patients’ benefit. Number of clinical trials is growing every year and fortunately no serious evidence for adverse events or other risks for subjects’ health and well-being was found up-to-date.
\nTherapeutic angiogenesis has become one of the pioneer methods in translational medicine and its full potential is yet to be unleashed especially in the field of ex vivo modification and tissue-engineered approaches to increase efficacy and ensure safety.
Study and publication was supported by a grant from Russian Scientific Foundation (RSF) №16-45-03007.
Please provide publisher name and location for ref. 14.
Please provide page number for reference 49.
Please complete and update the reference given here (preferably with a DOI if the publication data are not known): [101].
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), initiated in Wuhan in China, revisited 17 years later an outbreak that started in 2002 in China caused by a virus very similar to SARS-CoV-2 [1]. Identification and sequencing of the virus responsible for COVID-19 determined that it was a novel coronavirus that shared 88% sequence identity with two bat-derived SARS-like CoV, suggesting it’s origin in bats [2]. Additionally, it was shown that this coronavirus, which was termed 2019-nCoV or SARS-CoV-2, shared 79.5% sequence identity with SARS-CoV [2].
After inhalation of SARS-CoV-2, it invades nasal epithelial cells (superior respiratory tract) and type II pneumocytes through binding the SARS spike protein to angiotensin-converting enzyme 2 (ACE-2) receptors [3]. This complex is proteolytically processed by transmembrane protease serine 2 (TMPRSS2), leading to cleavage of ACE-2 and activation of the spike protein, thereby facilitating viral entry into the target cell. For SARS-CoV-2 entry into a host cell, its spike protein needs to be cleaved by cellular proteases at 2 sites, termed S protein priming by the serine protease TMPRSS2, then the viral and cellular membranes can fuse [4]. It has been suggested that cells in which both ACE-2 and TMPRSS2 are expressed are most susceptible to entry by coronaviruses from the SARS family, among which is the virus described to cause SARS and, also SARS-CoV-2 [4, 5].
In relation to the mechanism of infection, the infected cells trigger the host’s immune response, and the inflammatory cascade is initiated by innate immune cells, being the host environment extremely important for internalization and multiplication of the virus [6]. Possible mechanisms of receptor and signaling mechanisms responsible for induction of inflammatory mediators, such as cytokines or chemokines, may be related to the release of danger signal molecules, like certain cytokines, or may be involve a different recognition pathway mediated by immune cells throughout known pattern recognition receptors, such as toll-like receptors (TLRs) [7].
The heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells may contribute to different susceptibility to severity of SARS-CoV-2 [7, 8]. Furthermore, the changes in metabolic and endocrine pathways associated with SARS-CoV-2 infection may untangle a more profound understanding of this disease and contribute to a more adequate response.
Although the SARS-CoV-2 infection is highly associated to respiratory infection, it is also true, that this infection reflects a systemic involvement with multiple symptoms, including fever, persistent dry cough, shortness of breath, chills, muscle pain, headache, loss of taste or smell, and gastrointestinal symptoms [9]. Interestingly, according to the clinical features of individuals affected with SAR-CoV-2, a significant proportion of patients initially present some atypical gastrointestinal symptoms such as diarrhea, nausea, and vomiting [10].
Coronaviruses are one of many pathogens known to cause postinfectious olfactory dysfunction, nasal epithelial cells and mainly goblet cells in a high expression patterns of the ACE-2 receptor, which is required for SARS-CoV-2 entry. Olfactory dysfunction and anosmia are highly implicated in SARS-CoV-2 infection. The inclusion of loss of smell or taste among these symptoms follows the emergence of evidence suggesting that SARS-CoV-2 frequently impairs the sense of smell. Olfactory disfunction, defined as reduced or distorted ability to smell during sniffing (orthonasal olfaction) or eating (retronasal olfaction), is often reported in mild or even asymptomatic cases [11]. There have also been reports of acute-onset (sudden) anosmia, sometimes in the absence of other symptoms, as a marker of SARS-CoV-2 [12].
Disruption of cells in the olfactory neuroepithelium may result in inflammatory changes that impair olfactory receptor neuron function, cause subsequent olfactory receptor neuron damage, and/or impair subsequent neurogenesis [13]. Such changes may cause temporary or longer-lasting olfactory disease.
Inflammatory signaling molecules are released by infected cells and alveolar macrophages in addition to recruited T lymphocytes, monocytes, and neutrophils. Subsequently the integrity of the alveolar-capillary membrane is compromised by the inflammatory response triggered by SARS-CoV-2 [14]. In the late stage, pulmonary edema can fill the alveolar spaces with hyaline membrane formation, compatible with early-phase acute respiratory distress syndrome [14], bradykinin may contribute to this pulmonary edema [15].
Another contribution for systemic reaction of SARS-CoV-2 infection is the nasal gene expression of ACE-2. Indeed, the lower rates of SARS-CoV-2 infection were found in children. From nasal epithelial samples collected as part of a study involving patients with asthma from 2015 to 2018, a comprehending a cohort of 305 patients aged 4 to 60 years, evidenced that the lower expression of ACE-2 in the nasal epithelium were found in younger children and ACE-2 expression was higher with each subsequent age group after adjusting for sex and asthma [16]. Yet, a recent study bring some data that children may be a potential source of contagion in the SARS-CoV-2 in spite of milder disease or lack of symptoms, and immune dysregulation is implicated in severe post-infectious multisystem inflammatory syndrome in children [17].
Overexpression of human ACE-2 enhanced disease severity of SAR-CoV-2 infection, being the lung injury aggravated by the presence of SARS-CoV spike. Interestingly, in mice model, the lung injury was attenuated by blocking the renin-angiotensin pathway and depended on ACE-2 expression [18].
In contrast to other coronaviruses, SARS-CoV-2 became highly lethal because the virus deregulates a lung protective pathway. About 83% of cells that express ACE-2 were alveolar epithelial type II cells (AECII), suggesting that those cells can serve as a reservoir for viral invasion [19]. In addition, gene ontology enrichment analysis showed that the expression ACE-2 by AECII have high levels of multiple viral process-related genes, including regulatory genes for viral processes, viral life cycle, viral assembly, and viral genome replication, suggesting that the ACE2-expressing AECII facilitate viral replication in the lung [20].
Expression of the ACE-2 receptor is also found in many extrapulmonary tissues including heart, kidney, and intestine [21]. In human lung, the ACE-2 is expressed in endothelial and smooth muscle cells of large and small blood vessels, and in alveolar and bronchial epithelial cells.
Contrarily to ACE-1, the ACE-2 is barely present in the circulation, but widely expressed in mentioned organs. Although ACE-2 is more related to the physiopathology of SARS-CoV, ACE-1 converts angiotensin I into angiotensin Ang II, then ACE-2 break down angiotensin II into molecules that counteract angiotensin II, but if the virus occupies the ACE-2 ‘receptor’ on the surface of cells, then its role is blunted [22]. Angiotensin I, can cause vasoconstriction, inflammation, and fibrosis by signaling through angiotensin II type 1 receptors. ACE-2 cleave angiotensin II to angiotensin 1–7, which can suppress inflammation and fibrosis and generate vasodilation by binding to the mas receptor (Figure 1a) [23, 24, 25, 26].
Integrative schematic diagram of the role of ACE (ACE-1), ACE-2 and collectrin in the renin–angiotensin system (a) (adapted from [30]) and the impact of RAS inhibition in SARS-CoV-2 infection (b) [31].
Moreover, ACE-2 is a negative regulator of the renin-angiotensin system (RAS), and functions as the key SARS coronavirus receptor and stabilizer of neutral amino acid transporters [27]. As previously mentioned, the ACE-2 catalyzes the conversion of angiotensin II to angiotensin 1–7, thereby counterbalancing ACE activity, and converts angiotensin I to generate angiotensin 1–9 [3]. The RAS is an acute phase pathway involved in the multisystemic response of cardiovascular and hematopoietic systems, maintenance of blood pressure homeostasis, as well as fluid and salt balance in mammals [28]. Abnormal activation of RAS has been associated with the pathogenesis of cardiovascular and renal diseases such as hypertension, myocardial infarction and heart failure. Therefore, these disorders share underlying pathophysiology related to the RAS and COVID19 that may be clinically insightful [29].
Cardiovascular disease and pharmacologic RAS inhibition both increase ACE-2 levels, which may increase the virulence of SARS-CoV-2 within the lung and heart, since the receptor of the two viruses is the same enzyme protein of the cell membrane [32]. Conversely, mechanistic evidence from related coronaviruses suggests that SARS-CoV-2 infection may downregulate ACE-2, leading to toxic over accumulation of angiotensin II that induces acute respiratory distress syndrome and fulminant myocarditis [33]. Therefore, RAS inhibition could mitigate this effect [34]. ACE-2 genetic variants may determine the circulating angiotensin 1–7 levels only in hypertensive females that probably had dose effects related to the localization in the X Chromosome of ACE-2 gene [35].
The bradykinin-kallikrein system can further contribute to local vascular leakage leading to angioedema, due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. The RAS is needed to inactivate des-Arg9 bradykinin, which is a potent ligand of the B1R [15]. In the late stage, pulmonary edema can fill the alveolar spaces with hyaline membrane formation, compatible with early-phase acute respiratory distress syndrome.
Other aspect to be pointed out is collectrin (Figure 1a), an homolog of ACE-2, that have been identified as essential molecules required for expression of neutral amino acid transporters on the cell surface of epithelial cells. Collectrin (Tmem27) is a transmembrane glycoprotein that is highly expressed in the kidney and vascular endothelium [36]. Furthermore, concordant with metabolic and endocrine changes associated with SARS-CoV-2 infection, collectrin might also have a role in insulin secretion in pancreatic β-cells and/or growth of islet cells [37].
Detailing the mechanism of ACE-1 and its possible role in SARS-CoV-2, ACE-1 has pleiotropic actions involving the cardiovascular and hematopoietic systems [23, 24, 25]. The two catalytic domains of ACE-1 has different affinities for its promiscuous substrates respectively in the N domain for goralitide or N-acetyl-seryl-aspartyl-lysyl-proline (NacSDKP), an inhibitor of hematopoiesis and fibrogenesis and that have influence on blood pressure predominantly the C-domain for Angiotensin I or for both domains as is the case of Bradykinin [25, 27].
Unpublished results from our group reflected an inverse correlations of ACE activity with antioxidant erythrocyte and plasma activity enzymes, and direct correlation with lower relative concentrations of glutathione associated to proinflammatory conditions like obesity and several autoimmune diseases (Figure 2).
Correlation between ACE and transmembrane redox system (a), erythrocyte methaemoglobin reductase (b), plasma epinephrine oxidase (c) and with plasma ratio of oxidized glutathione to reduced glutathione (d).
In terms of detection of SARS-CoV-2, the RT-PCR is a cheaper, easier and short turn-around time method for detection of RNA component of SARS-CoV-2, in upper respiratory samples, comparing with sequencing technology. Considering the genetic variability, the ACE-1 Insertion/Deletion (I/D) functional polymorphism influence its activity in plasma as it was reported by us and other authors (Figure 3a) [23, 38]. However, the ACE I/D polymorphism is not associated with increased susceptibility or poor outcome after SARS-CoV-1 infection [39]. Paradoxically, in studies on longevity from our and other groups, individuals with DD genotype, with higher activities of ACE, are more represented in centenarians [40, 41].
Distribution of ACE activity according to ACE (a) and SERT (serotonin transporter) (b) genotypes.
The response to this pathway when exaggerated, as is the case of the SARS-CoVs infections, causes intense inflammatory and fibrogenic processes. On the contrary, the system initiated by ACE-2 also has pleiotropic antagonistic actions of the classic system and it has an anti-inflammatory and anti-fibrogenic system [42]. Furthermore, both systems have functional polymorphic genetic variations [23, 38, 39, 43, 44, 45].
Genetic polymorphisms in the RAS are putative markers prone to affect the clinical course of SARS-CoV-2 infection. Cao et al. in 2020 suggested that ACE-2 and SARS-CoV-2 associated frequencies among populations can be justified by allele sequences distributions. The greatest are in East Asians populations with higher expressions in tissues that suggest different susceptibilities or response to SARS-CoV-2 in different ecosystems [44].
As previously mentioned, the major clinical complication in patients with SARS-CoV-2 is respiratory failure due to local hyperinflammation and acute respiratory distress syndrome. The pathophysiology of these complications has strong similarities to other severe viral lung infections, such as influenza, and other infections caused by coronaviruses (SARS and Middle East respiratory syndrome). An important mechanism mediating lung pathology in these infections is a cytokine storm leading to the so-called “macrophage activation syndrome” with crucial role for monocytes and macrophages [46, 47].
Accordingly with the major clinic complications of this infection, this extreme inflammation compromises the respiratory performance, which often requires ventilator support or, even, extracorporeal membrane oxygenation [48]. However, in approximately 80% of cases, the latter did not prevent mortality, owing to insufficient lung perfusion, which could be explained by developing thromboembolic complications. In this context, clinical trials are underway to determine whether anticoagulants (e.g., heparin) or profibrinolytic drugs (e.g., tissue plasminogen activator) ameliorate severe infection with thromboembolic complications [30, 49].
From the inflammatory perspective, these infection leads to changes in circulating concentrations of proinflammatory cytokines, such as interleukin (IL)-6, tumor necrosis factor (TNF), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein 1-alpha (MIP1A), and interferon gamma-induced protein 10 (IP10), comparing patients in intensive care unit (ICU) and to those who do not need treatment in the ICU, although the concentrations of some of these cytokines are only moderately increased [50]. This strong increase in systemic inflammation is associated with endothelial dysfunction, increased coagulation activity reflected by elevated d-dimers [50] and hyperactive CCR6 + Th17+ T cells locally in the lung [9]. The increase in systemic concentrations of proinflammatory cytokines was minimal, even during days 7–9, when the patient was symptomatic. This suggests that a mild course of infection is associated with few systemic inflammatory effects. Still, the hyper-inflammation occurs in SARS-CoV-2 and is associated with worse outcomes [48].
Gender differences have been widely discussed in different pathologies, indeed these differences may reflect sex chromosome genes and sex hormones, including estrogens, progesterone, and androgens, with implications to the differential regulation of immune responses between the genders [51]. In studies of hypertension, there is a clear difference between genders taking on account the distribution of ACE-2 genetic polymorphisms associated levels of angiotensin 1-7 [52].
Concerning SARS-CoV-2 infection, a male bias in mortality has emerged in the COVID-19 pandemic, which is consistent with the pathogenesis of other viral infections. Biological gender differences may manifest themselves in susceptibility to infection, early pathogenesis, innate viral control, adaptive immune responses or the balance of inflammation and tissue repair in the resolution of infection [53]. The differences in immune response according with gender, suggest less robust T cell-mediated immunity in male patients with worsening outcome and higher innate cytokine activity, compared to female patients [54].
Evidence reflected the gender as an important driver of risk of mortality and response to the SARS-CoV-2 pandemic. The sex differences in SARS-CoV-2 mortality, severity and recovery, may underly implications of cardiovascular disease (CVD) risk factors, reflecting a plausible biological reasons for this sex difference in SARS-CoV-2 infection [55]. This disproportionate death ratio in men may partly be explained by their relatively higher contribution of pre-existing diseases (i.e., CVD, hypertension, diabetes, and chronic lung disease), higher risk behaviors (i.e., smoking and alcohol use), and occupational exposure [55]. There may be other behavioral and social differences that favor women, with prior studies suggesting women are more likely than men to follow hand hygiene practices and seek preventive care [55].
The host metabolism supports viral pathogenesis by fueling viral proliferation, by providing free amino acids and fatty acids as building blocks. Alterations in tryptophan metabolism and kynurenine pathway regulates inflammation and immunity [56]. The indolamine-2, 3-dioxygenase (IDO) is an intracellular, non-secreted enzyme, which catabolizes kynurenine from tryptophan with interesting role in viral and bacterial infections [57]. Since many microbial organisms rely on the essential amino acid tryptophan, its degradation by IDO-expressing cells of the innate immune system was favored as the major IDO-mediated mechanism against infections [58]. In infectious disease states, IDO has been shown to exert pleiotropic effects, even with opposing outcomes. IDO prevents viral spread and from host perspective also acts to suppress immune reactions thereby promoting infectious diseases [56, 59].
Tryptophan metabolism was the top pathway affected by SARS-CoV-2. As such, focused analysis of this pathway highlighted significant decreases (inversely proportional to IL-6 concentration) in tryptophan, serotonin, and indolepyruvate levels. In contrast, increases in kynurenine, kynurenic acid, picolinic acid, and nicotinic acid suggested hyperactivation of the kynurenine pathway [58]. Furthermore, the levels of IL-6 in serum were significantly different from SARS-Cov-2 patients and controls and they were correlated with changes in tryptophan metabolism [58]. From this study, targeted metabolomics analyses were performed on sera using ultra-high-pressure liquid chromatography-mass spectrometry (UHPLC–MS), highlighting significant associations of COVID-19 and IL-6 levels with amino acid metabolism, purines, acylcarnitines, and fatty acids [58]. Dysregulation of nitrogen metabolism was also seen in infected patients, with altered levels of most amino acids, along with increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and renal dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis. Interestingly, metabolite levels in these pathways correlated with clinical laboratory markers of inflammation (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen). This initial observational study identified amino acid and fatty acid metabolism as correlates of SARS-CoV-2 [58].
In our group, we also demonstrated that a functional variable number of tandem repeats (VNTR) genetic polymorphism of serotonin transporter, whose expression is activated by IL-1, has some relation with the ACE serum levels that can be associated with unbalanced ACE-ACE-2 system (Figure 3b) [38].
Polymorphisms in genes coding for IL-10, TNF-alpha and IL-6 influence circulating levels, and behave as promoters of severe systemic inflammatory response that can probably has an interindividual and gender dependent impact [53].
At the other end of the iceberg, the immunocompromised patients could be protected against SARS-CoV-2, since unlike other common viruses, coronaviruses have not shown to cause more severe disease in immunosuppressed patients, at least statistically significant [60]. Our own immune response appears to be the main driver of lung tissue damage during infection. Starting around the 2nd week of symptoms, patients experience a “storm of cytokines” – autoimmune reaction, where your body over-reacts and in attacking coronavirus, your lungs get caught in the body immunologic response [47, 61]. In the first week of the illness it’s the virus itself that’s triggering most of your symptoms, but then in severe cases, it’s our own inflammatory responses that takes over in causing the most of the damage. So this “storm of cytokines” is killing our immune cells, therefore, could patients with immunosuppressive profile be protected from this reciprocal attack?
The children account for less than 2% of identified cases of SARS-CoV-2 [62]. Interestingly, young children, including infants who are more susceptible to other infections, have milder symptoms and less severe SARS-CoV-2. Nevertheless, children seem to have similar rates of becoming infected compared with middle-aged adults following close contact with a person infected with SARS-CoV-2 [33].
Long-term boosting of innate immune responses, also termed “trained immunity,” by certain live vaccines (Bacillus Calmette–Guérin - BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells [63].
Epidemiological data showed that the elderly and those with co-morbidities (diabetes, obesity, and cardiovascular, respiratory, renal, and lung diseases) are most susceptible to COVID-19 and more likely to suffer from the most severe disease complications [64]. Viral infections mobilize free fatty acids to support capsid-associated membrane formation, which was described for other coronaviruses and is explained, in part, by activating phospholipase A2, a target amenable to pharmacological intervention [65].
Hartnup disease is a condition caused by the body’s inability to absorb certain protein building blocks (amino acids) from the diet. As a result, affected individuals are not able to use these amino acids to produce other substances, such as vitamins and proteins. Most people with Hartnup disease are able to get the vitamins and other substances they need with a well-balanced diet [27, 66].
Individuals with Hartnup disease have high levels of various amino acids in their urine (aminoaciduria). For most affected individuals, this is the only sign of the condition. However, in other cases, individuals have episodes exhibiting other signs, which can include skin rashes, difficulty of coordination of movements (cerebellar ataxia), and psychiatric symptoms, such as depression or psychosis. These episodes are typically temporary and are often triggered by intercurrent infection, stress, nutrient-poor diet, or fever. These features tend to go away once the trigger is changed, although the aminoaciduria remains. In affected individuals, signs and symptoms most commonly occur in childhood [67, 68].
As previously mentioned, the two antagonistic systems ACE, ANG II, AT1R and ACE2, ANII 1–7 are in the “hurricane eye” of SARS-CovV-2 and the non-enzymatic role of ACE-2 give rise to Hartnup disease phenocopy. ACE-2 is also a stabilizing protein (very similar to collectrin in kidney) of the neutral amino acid transporter mutated in the Hartnup disease [27].
In mice with ACE-2 deletion in the small intestine, there was also a decrease in tryptophan absorption secondary to the lower expression of the neutral amino acid transporter accompanied by a phenotype very similar to that of Hartnup’s disease phenotypes [69]. This situation can be caused by SARS-COVs and probably explains the gastro intestinal symptoms sometimes associated with those viral infections. In this case, it may be the result of the accumulation of nephrotoxic and pro-inflammatory pulmonary products (indole derivatives) or lack of anti-inflammatory kynurenines (IDO derivatives), as a consequence of dysbiosis at large intestine resulting from the lack of absorption of several neutral and aromatic amino acids namely tryptophan [70, 71].
Concordantly to exposed in this chapter, the SARS-CoV-2 is more than a severe respiratory infection and actually integrate a multisystemic coordination. Metabolic syndrome and microbiome had been associated in intervention from ACE-2. This relation has an explanation that is now much more clarified and that goes through the IDO derivatives (Kynurenines) associated with aryl hydrocarbon receptor (AhR) and anti-inflammatory response Th22 [56].
The rationale of the non-enzymatic role of ACE-2 to serotonin and IDO derivatives to kynurenines has an explanation based in the activation of AhR functions by these tryptophan metabolites as they activates anti-inflammatory cytokines that may counteract the SARS-CoV-2 gastrointestinal and pulmonary symptoms characterized by a “cytokine storm” [72]. This can have their origin in the dysbiosis related to the tryptophan catabolism in indol derivatives by unbalanced Lacobacillus spp (decreased) specially in high salt microenvironment characteristic of western pattern diets [71, 73, 74].
Importantly, ACE-2 is highly expressed on the luminal surface of intestinal epithelial cells, functioning as a co-receptor for nutrient uptake, in particular for amino acid resorption from food [75]. Therefore the intestine might also be a major entry site for SARS-CoV-2 and the infection might have been initiated by eating food from the Wuhan market, the putative site of the outbreak. Whether SARS-CoV-2 can indeed infect the human gut epithelium has important implications for fecal–oral transmission and containment of viral spread. Moreover, the ACE-2 tissue distribution in other organs could explain the multi-organ dysfunction observed in patients [66, 71, 76, 77]. Any perturbation in host-microbiota crosstalk can be an initiating or re-enforcing factor in SARS-CoV-2 pathogenesis.
Some bacteria produce bioactive neurotransmitters that have previously been proposed to modulate nervous system activity and behaviors of their host. A large array of metabolites drives the crosstalk between the host and its microbiome. The three currently most studied categories of metabolites involved in host-microbiota interactions are short-chain fatty acids produced by bacteria from the fermentation of fibbers, bile acids produced in the liver and transformed by the gut microbiota before re-affecting the host, and tryptophan metabolites, which are the topic of this review [72].
Tryptophan is an essential aromatic amino acid composed of a b carbon connected to the 3 position of an indole group and it is a biosynthetic precursor of a large number of microbial and host metabolites [78]. It’s metabolism follows three major pathways in the gastrointestinal tract: the direct transformation of Tryptophan into several molecules, including ligands of the (AhR) by the gut microbiota [78]; the kynurenine pathway in both immune and epithelial cells via IDO-1 [79]; and the serotonin (5-hydroxytryptamine [5-HT]) production pathway in enterochromaffin cells via Tryptophan hydroxylase 1 (TpH1) [72]. The AhR is implicated in lung inflammation [80].
The gut microbiota influences the health of the host, especially with regard to gut immune homeostasis and the intestinal immune response. In addition to serving as a nutrient enhancer, L-tryptophan plays crucial roles in the balance between intestinal immune tolerance and gut microbiota maintenance.
These lessons derived of SARS-CoVs infections outbreaks (2003 and 2019) can explain the role of the two antagonistic RASs pathways on the hypoxic pulmonary vasoconstriction an homeostatic mechanism in response to alveolar hypoxia secondary to acute lung injury in SARS, optimizing ventilation, perfusion and systemic oxygen delivery. Moreover, the new knowledge about the role of RAS proteins, namely, ACE-2 in gut with pleiotropic actions on the metabolism of tryptophan in the crosstalk microbiota–intestine, intestine-kidney and probably intestine-lung can help in designing new, based on probiotics and prebiotics or repurposing ancient therapies for disorders involving those organ crosstalk resultant physio pathologies.
The authors would like to acknowledge the Instituto de Investigação Científica Bento da Rocha Cabral and Sociedade Portuguesa de Papillomavírus for support.
The authors declare that they have no competing interests.
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I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. 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