Comparison of different strategies for iPSC generation
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-partners-with-ehs-for-digital-advertising-representation-20210416",title:"IntechOpen Partners with EHS for Digital Advertising Representation"},{slug:"intechopen-signs-new-contract-with-cepiec-china-for-distribution-of-open-access-books-20210319",title:"IntechOpen Signs New Contract with CEPIEC, China for Distribution of Open Access Books"},{slug:"150-million-downloads-and-counting-20210316",title:"150 Million Downloads and Counting"},{slug:"intechopen-secures-indefinite-content-preservation-with-clockss-20210309",title:"IntechOpen Secures Indefinite Content Preservation with CLOCKSS"},{slug:"intechopen-expands-to-all-global-amazon-channels-with-full-catalog-of-books-20210308",title:"IntechOpen Expands to All Global Amazon Channels with Full Catalog of Books"},{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"}]},book:{item:{type:"book",id:"1760",leadTitle:null,fullTitle:"The Role of Osteotomy in the Correction of Congenital and Acquired Disorders of the Skeleton",title:"The Role of Osteotomy in the Correction of Congenital and Acquired Disorders of the Skeleton",subtitle:null,reviewType:"peer-reviewed",abstract:"This book demonstrates specific osteotomy techniques from the skull to the hallux. The role of osteotomy in the correction of deformity is under appreciated in part because of the ubiquitous nature of joint replacement surgery. It should be remembered, however, that osteotomy has a role to play in the correction of deformity in the growing child, the active young adult, and patients of any age with post-traumatic deformity limiting function and enjoyment of life.\nIn this text we bring you a number of papers defining specific problems for which osteotomy is found to be an effective and lasting solution. I hope you find it useful.",isbn:null,printIsbn:"978-953-51-0495-7",pdfIsbn:"978-953-51-4302-4",doi:"10.5772/2196",price:139,priceEur:155,priceUsd:179,slug:"the-role-of-osteotomy-in-the-correction-of-congenital-and-acquired-disorders-of-the-skeleton",numberOfPages:306,isOpenForSubmission:!1,isInWos:1,hash:"9661cdebd682842816ac472a9330e6eb",bookSignature:"James P. 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He did his postgraduate training in orthopaedic surgery at the University of Toronto and assumed a staff position at St. Michael’s Hospital in 1973. \n\nHe has occupied a number of positions at St. Michael’s Hospital including Surgeon-in-Chief and Medical Director of the Trauma Program; he completed 10 years as the Professor & Chairman, Division of Orthopaedic Surgery at University of Toronto in June of 2006. He has also occupied a number of positions in the Canadian Orthopaedic Association including President. He has completed a 10 year term as the Co-Editor of the Canadian Journal of Surgery. \n\nHe is currently the Chair of the Expert Panel for Orthopaedic Surgery for the Province of Ontario and the Coordinator for the National Action Network for the Bone & Joint Decade in Canada. He also is the Co-Chair of the National Hip and Knee Knowledge Translation Network and the Board Chair for the Canadian Orthopaedic Foundation.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"St. Michael's Hospital",institutionURL:null,country:{name:"Canada"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1144",title:"Craniofacial Surgery",slug:"craniofacial-surgery"}],chapters:[{id:"35329",title:"Surgery of the Bony and Cartilaginous Vault in Rhinoplasty",doi:"10.5772/36520",slug:"surgery-of-the-bony-and-cartilaginous-vault",totalDownloads:5651,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Pavel Dolezal",downloadPdfUrl:"/chapter/pdf-download/35329",previewPdfUrl:"/chapter/pdf-preview/35329",authors:[{id:"108647",title:"Dr.",name:"Pavel",surname:"Doležal",slug:"pavel-dolezal",fullName:"Pavel Doležal"}],corrections:null},{id:"35330",title:"Le Fort I Osteotomy for Maxillary Repositioning and Distraction Techniques",doi:"10.5772/37211",slug:"le-fort-i-osteotomy-for-maxillary-repositioning-and-distraction",totalDownloads:43164,totalCrossrefCites:2,totalDimensionsCites:10,signatures:"Antonio Cortese",downloadPdfUrl:"/chapter/pdf-download/35330",previewPdfUrl:"/chapter/pdf-preview/35330",authors:[{id:"111774",title:"Prof.",name:"Antonio",surname:"Cortese",slug:"antonio-cortese",fullName:"Antonio Cortese"}],corrections:null},{id:"35331",title:"Quality Control of Reconstructed Sagittal Balance for Sagittal Imbalance",doi:"10.5772/37713",slug:"quality-control-of-reconstructed-sagittal-balance-for-sagittal-imbalance",totalDownloads:2283,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Kao-Wha Chang",downloadPdfUrl:"/chapter/pdf-download/35331",previewPdfUrl:"/chapter/pdf-preview/35331",authors:[{id:"114023",title:"Dr.",name:"Kao-Wha",surname:"Chang",slug:"kao-wha-chang",fullName:"Kao-Wha Chang"}],corrections:null},{id:"35332",title:"Pelvic and Hip Osteotomies in Children",doi:"10.5772/37956",slug:"pelvic-and-hip-osteotomy-in-children",totalDownloads:6266,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"I. 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Since the first years of the introduction of cocaine by Carl Koller in 1884, the evolution of regional anesthesia has been continuous, gradual and safe. Its development has been based on anatomy, the pharmacology of local anesthetics and adjuvant drugs, as well as advances in the various blocking techniques, with ultrasound guidance being the most recent advent. The use of ultrasound in regional anesthesia has shown the reduction of complications, which makes it mandatory to knowledge and acquire skills in all ultrasound-guided techniques.
\r\n\r\n\tUltrasound-guided regional blocks will be reviewed extensively, as well as intravenous regional anesthesia, thoracic spinal anesthesia. The role of regional anesthesia and analgesia in critically ill patients is of paramount importance. In addition, we will review the current role of regional techniques during the Covid-19 pandemic. Complications and malpractice is another topic that should be reviewed. Regional anesthesia procedures in some specialties such as pediatrics, orthopedics, cancer surgery, neurosurgery, acute and chronic pain will be discussed.
",isbn:"978-1-83969-570-4",printIsbn:"978-1-83969-569-8",pdfIsbn:"978-1-83969-571-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"264f7f37033b4867cace7912287fccaa",bookSignature:"Prof. Víctor M. Whizar-Lugo, Dr. José Ramón Saucillo-Osuna and Dr. Guillermo A. Castorena-Arellano",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10708.jpg",keywords:"Regional Anesthesia, Ultrasound-Guided Regional Anesthesia, Local Anesthetics, Preventive Analgesia, Peripheral Blocks, Pediatric Regional Anesthesia, Intravenous Regional Anesthesia, Techniques, Complications, Adjuvants in Regional Anesthesia, Opioids, Alfa2 Agonists",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 25th 2021",dateEndSecondStepPublish:"March 25th 2021",dateEndThirdStepPublish:"May 24th 2021",dateEndFourthStepPublish:"August 12th 2021",dateEndFifthStepPublish:"October 11th 2021",remainingDaysToSecondStep:"23 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Whizar-Lugo has published more than 100 publications on Anesthesia, Pain, Critical Care, and Internal Medicine. He works as an anesthesiologist at Lotus Med Group and belongs to the Institutos Nacionales de Salud as an associated researcher.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"169249",title:"Prof.",name:"Víctor M.",middleName:null,surname:"Whizar-Lugo",slug:"victor-m.-whizar-lugo",fullName:"Víctor M. Whizar-Lugo",profilePictureURL:"https://mts.intechopen.com/storage/users/169249/images/system/169249.jpg",biography:"Víctor M. Whizar-Lugo graduated from Universidad Nacional Autónoma de México and completed residencies in Internal Medicine at Hospital General de México and Anaesthesiology and Critical Care Medicine at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in México City. He also completed a fellowship at the Anesthesia Department, Pain Clinic at University of California, Los Angeles, USA. Currently, Dr. Whizar-Lugo works as anesthesiologist at Lotus Med Group, and belongs to the Institutos Nacionales de Salud as associated researcher. He has published many works on anesthesia, pain, internal medicine, and critical care, edited four books, and given countless conferences in congresses and meetings around the world. He has been a member of various editorial committees for anesthesiology journals, is past chief editor of the journal Anestesia en México, and is currently editor-in-chief of the Journal of Anesthesia and Critical Care. Dr. Whizar-Lugo is the founding director and current president of Anestesiología y Medicina del Dolor (www.anestesiologia-dolor.org), a free online medical education program.",institutionString:"Institutos Nacionales de Salud",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"3",institution:null}],coeditorOne:{id:"345887",title:"Dr.",name:"José",middleName:"Ramon",surname:"Saucillo",slug:"jose-saucillo",fullName:"José Saucillo",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000033rFXmQAM/Profile_Picture_1611740683590",biography:"Graduated from the Facultad de Medicina de la Universidad Autónoma de Guadalajara, he specialized in anesthesiology at the Centro Médico Nacional de Occidente in Guadalajara, México. He is one of the most important pioneers in Mexico in ultrasound-guided regional anesthesia. Dr. Saucillo-Osuna has lectured at multiple national and international congresses and is an adjunct professor at the Federación Mexicana de Colegios de Anestesiología, AC, former president of the Asociación Mexicana de Anestesia Regional, and active member of the Asociación Latinoamericana de Anestesia Regional.",institutionString:"Asociación Latinoamericana de Anestesia Regional",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:{id:"346513",title:"Dr.",name:"Guillermo A.",middleName:null,surname:"Castorena-Arellano",slug:"guillermo-a.-castorena-arellano",fullName:"Guillermo A. Castorena-Arellano",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000034VWIyQAO/Profile_Picture_1611740569514",biography:"Graduated from Universidad Nacional Autónoma de México, completed his residency in Internal medicine, Anesthesia and Critical care at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in México City. Fellowship in Intensive respiratory therapy at the Massachussets General Hospital Harvard Medical School in Boston, USA. Currently, he is professor of anesthesiology at the Fundación Clínica Médica Sur-UNAM. Dr Castorena-Arellano has many publications on anesthesia, internal medicine and critical care journals/books, edited a book on perioperative medicine, and has given numerous conferences in congresses and meetings around the world. He is an active member of several medical societies in Europe and America.",institutionString:"Fundación Clínica Médica Sur-UNAM",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"347258",firstName:"Marica",lastName:"Novakovic",middleName:null,title:"Ms.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"marica@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"3819",title:"Topics in Spinal Anaesthesia",subtitle:null,isOpenForSubmission:!1,hash:"d7bf34d33972bf5002ed97828eb508ad",slug:"topics-in-spinal-anaesthesia",bookSignature:"Victor M. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"41853",title:"Multiple Paths to Reprogramming",doi:"10.5772/55104",slug:"multiple-paths-to-reprogramming",body:'For a long time, differentiation was considered a “one way process”; Conrad Waddington, in the 1950s, described cellular differentiation and development as a ball rolling towards different one-way ramified valleys, giving rise to specific cell fates, irreversibly [1]. However, in the last decades, a series of studies have shown that somatic cells and stem cells are more plastic than previously believed. Using different technical approaches, the epigenetic barriers imposed during development in differentiated cells can be erased, and cells can re-acquire pluripotency through a process, known as “reprogramming”.
The first evidence came at the end of the 1950’s from the pivotal experiments performed by J.B. Gordon in the zoology department at Oxford University [2]. At that time, embryologists, not aware of epigenetic regulation, i.e. the role of chromatin and its crucial modifications in cell fate determination, wondered whether development and cellular differentiation arise upon specific restriction of the genetic information contained in their nuclei. To answer this basic but intriguing question, Gordon used a technique, now known as somatic cellular nuclear transfer (SCNT) in
For forty years, the scientific community was not able to use SCNT in other species. Finally, in 1997, by using the same technique, Ian Wilmut and colleagues, at the Roslin Institute in Edinburgh, Scotland, succeeded in generating the sheep named “Dolly” by SCNT, further confirming that genetic modifications, leading to cellular differentiation, are not irreversible. Two key improvements in his technical strategy led to the first cloning of a mammal: unfertilized oocytes were used as recipients and donor cells were induced to exit from the normal cellular cycle, by serum withdrawal [4, 5].
One year later, Wakayama and colleagues [6] reported that SCNT also allowed the cloning of the most used animal model, the mouse. Again, another technical advance led to this progress: the use of an enucleation pipette, which allowed for the removal of the nucleus from the oocytes. This advance also allowed the conclusion that reprogramming factors are not oocyte-specific, meaning that SCNT can be done also using zygotes and fertilized eggs [7], and that the molecules responsible for reprogramming were present in the cell cytoplasm. In general, nuclear transfer (see Figure 1) involves two steps: a) de-differentiation of a somatic donor cell to an embryonic state and the
SCNT, Therapeutic and Reproductive cloning
Therapeutic cloning permits the derivation of nuclear transfer derived embryonic stem cells (ntESCs). Recently, the efficiency of isolation of ntESCs drastically increased, at least in mice, from 1% to 20% [8]. It has also been possible to derive similar cells in cats, dogs, wolves, goats and monkeys. Although the isolation of human ntESCs has been reported, this paper has been retracted later on [9]. Thus, the possibility of therapeutic cloning with human cells needs to still be demonstrated. However, the therapeutic cloning remains a promising technology for regenerative medicine, considering that ntESCs, from other species, were able to differentiate into all the cell types of an adult body.
Reproductive cloning is technically more difficult than therapeutic cloning, as it involves the further development
Analysis of the cloned animals also showed several abnormalities: increased telomere shortening (which may have caused the premature death of Dolly), altered gene expression during development, prolonged gestation, fetal or placental edema, increased risk of obesity and cancer. The reasons for these pathologies remain not fully understood. The defects may be due to infidelity of the reprogramming: residual epigenetic memory of the donor cell may be present an/or imprinting of important developmental genes may be altered. Nevertheless, reproductive cloning remains attractive and may have potential implications in agriculture and industrial biotechnology. However, as it relates to humans, cloning (also therapeutic) remains controversial as theoretically, it may allow the cloning of a human being.
Evidence that differentiation is reversible also comes from another technique, known as cell fusion [10]. In cell fusion experiments, two or more cells can be fused together (by using polyethylene glycol (PEG) or electrofusion) to generate a single cell, called heterokaryon or hybrid. The larger or more dividing cell type is the “dominant” one, and the “recessive” cell will convert its gene expression profile to the one imposed by the dominant cell type. Obviously, alteration in the ratio of the two cell types during fusion will affect the final fate of the fused cells [11].
A heterokaryon, produced by inhibiting cell division, is a fused cell that becomes multinucleated and survives only short-term. If the cell cycle is not blocked, the fused cells will form a hybrid, because upon the first division the two different nuclei will become a single nucleus, having 4n chromosomes (see Figure 2). Its karyotype can be: 1) euploid, when fused cells are from same species (the two cell types have the same number of chromosomes, thus, their segregation will be balanced); 2) aneuploid, when cells fused are from different species (the two cell types have a different number of chromosomes, thus, they will be lost and/or rearranged).
Cell fusion
Cell fusion experiments advanced medical knowledge on cell plasticity. In 1969, Harris et al. fused tumor cells with normal cells and demonstrated that there are trans-acting oncosuppressor genes. Upon fusion, malignancy was suppressed and this was not due to the loss of an oncogene, as after prolonged
In 1983, Blau et al. [17] produced for the first time heterokaryons from diploid human amniocytes fused with differentiated mouse muscle cells. She demonstrated that the heterokaryons express many human muscle-related genes and that this activation was mediated by factors present in the cytoplasm (as non-dividing heterokaryons have distinct nuclei). Similar heterokaryons with muscle cells can be produced not only by fusing them with amniocytes but also with cells of the three embryonic lineages (mesoderm, ectoderm, endoderm) [18].
In 1997, Surani, Tada and colleagues demonstrated, by producing proliferative hybrids that cell fusion not only ”switches” the fate of different cell types but also “reprograms” them to a pluripotent state. Thymocytes from adult mice were fused to embryonic germ cells, pluripotent stem cells derived from primordial germ cells (PGCs). By using DNA sensitive restriction enzymes, they demonstrated that the genome of the somatic cell underwent a general demethylation, with reactivation of imprinted and non-imprinted genes, resembling the reprogramming events occurring in germ cell development [19].
They also fused female thymocytes, derived from Oct4-GFP mice, with mouse ESCs [17]. Two days after fusion, expression of GFP, from the thymocyte, was detected. The X chromosome, normally silenced in adult female cells, was reactivated. Moreover, hybrids had developmental potential, like ESCs, as they contributed to the three germ layers of chimeric animals, upon blastocyst aggregation [18]. Using the same approach, in 2005, Cowan succeeded in creating hybrids between human somatic cells and human ESCs [19].
This further elucidated that the differentiation state of cells is plastic and reversible; both SCNT and cell fusion experiments clearly demonstrated that it is possible to reset the epigenetic landscape of somatic cells. Despite all these studies were already present in the literature, the field of reprogramming only became jumpstarted in 2006 when Takahashi and Yamanaka [20] demonstrated that the overexpression of pluripotency-related transcription factors (TFs) can dedifferentiate adult fibroblasts to induced pluripotent stem cells (iPSCs), iPSCs strongly resemble ESCs. iPSC technology is an inefficient process, but differently from SCNT or cell fusion, may have in the near future therapeutic applications, including human disease modeling, drug screening and patient-specific cell therapy (see Figure 3).
After this publication [20], several studies demonstrated the potential of epigenetic reprogramming. Indeed, there is now evidence that use of different “cocktails” of TFs allows not only to redirect fibroblasts to an ESC-fate but also to a lineage-specific cell types/precursors, like cardiomyocytes, neuronal precursors, hepatocytes and blood cells, from a tissue different than the tissue from which the somatic cell was isolated [21-23].
iPSC technology and applications
Finally, It has also become clear that cell plasticity and reprogramming may be partially achieved or enhanced by the culture microenvironment. An increasing number of studies is showing how small molecules, including epigenetic modifiers and signaling pathway modulators, play a crucial role in cell-fate determination [24]. All together, these studies highlight that culture media influences the epigenetic-state of the cells in which they are cultured and thus their features [25]. In this chapter, we will discuss:
In 1987, two key discoveries highlighted how crucial the role is of some “master” TFs in cell fate determination. During
Twenty years after these pivotal experiments, Shinya Yamanaka’s group used the same TF-based technology to reprogram adult fibroblasts to pluripotent state [20]. Mouse embryonic and adult fibroblasts, transduced with retroviral vectors encoding for Oct4, Sox2, Klf4 and c-Myc and cultured in ESC-medium, erased their differentiated epigenetic state and reestablished the pluripotent state; these cells were named induced pluripotent stem cells (iPSCs). Murine iPSCs exhibited morphological and growth properties of ESCs, and expressed alkaline phosphatase and SSEA1. No differences, if compared with ESCs, could be detected in their methylation status, X activation status, embryoid body (EB) formation,
Noteworthy, pluripotent stem cells (PSCs) possess mechanisms that lead to the silencing of the integrated transgenes. Therefore, the expression of the four TFs is necessary for generating iPSCs but dispensable for maintenance of the iPSC fate; hence, pluripotency and selfrenewal capacity rely on the trans-activation of the endogenous genes, suggesting a true and complete reprogramming. Mouse iPSCs, like ESCs, were germline competent [28] and supported the development of a mice in tetraploid complementation assay [29]. In this assay, embryonic cells at the two cell-stage are fused together. This results in a tetraploid blastocyst in which just the extraembryonic tissues will further develop; by complementing the tetraploid embryo with normal diploid PSCs, it is possible to generate an individual, completely derived from the diploid PSCs. Interestingly, the same combination of TFs [30] or a somewhat different one (Oct4, Sox2, Nanog and Lin28) can be used for the reprogramming of human cells [31].
This discovery is groundbreaking because with iPSC technology, PSCs can now be induced/derived for autologous cell transplantation, avoiding immunological problems and ethical issues related to the use of human ESCs. In addition, iPSCs from patients carrying a disease can be derived and used to better understand the biological problem leading to the disease as well as for drug-screening.
The rationale for the selection of the genes for this “reprogramming” cocktail was obviously based on the studies, done in the preceding decade, aimed at understanding the network of TFs responsible for ESC pluripotency and selfrenewal.
The Oct4 (also known as Pou5f1) gene encodes for a TF that belongs to the POU homeodomain DNA binding domain family [32]. It plays a key role in the development and in maintenance of both ESCs self-renewal and pluripotency. Misregulation of its levels triggers loss of the ESC fate; a 50% loss of expression drives ESCs to trophectoderm while a 50% greater expression induces primitive endoderm or mesoderm [33]. Knockout (KO) experiments in mouse demonstrated lethality at the preimplantation stage
Sox2 belongs to a family of TFs, having the high mobility group (HMG) DNA-binding domain, identified for the first time in the SRY (sex determining Y region) protein, which is the testis determining factor. In general, the genes from the Sox family are involved in different and crucial steps of mammalian development [35, 36]. Sox2 KO embryos die immediately after implantation [37]. Moreover, it is well known that Oct4 and Sox2 form a complex together, which regulates synergistically the trascription of among others, Fbx15, Fgf4 and Utf1 [38-41].
Nanog, (from Tír na nÓg, the Land of Ever-Young in the old Irish mythology) is another homeobox TF essential for pluripotency. Nanog expression can be detected in the late morula, in the ICM of the blastocyst and in the epiblast. Nanog knockout mice are lethal and the ICM fails to further progress to the epiblast-stage [42-44]. In contrast to Oct4, Nanog overexpression maintains ESC selferewal and pluripotency in a feeder-free and LIF-independent way.
Lin28 is a negative regulator of micro (mi)RNA processing. It blocks the posttranscriptional processing of several primary miRNA transcripts (pri-miRNAs). It is responsible for miRNA biogenesis in both cancer cells and ESCs; so it plays a key role in tumorigenesis and development. Lin28 KO mice have decreased weight at birth and increased postnatal lethality [45].
Different from the above genes, Klf4 and c-Myc are not ESC-specific but are required for their direct or indirect effect on cell proliferation. Of note, iPSCs can also be produced without c-Myc and this is clinically relevant, considering the oncogenic features of c-Myc [46].
Although the combination of Oct4, Sox2, Klf4 and c-Myc (OSKM) consistently allows the reprogramming, this it is not an efficient process (0.01-0.1%). For this reason, subsequent studies were focused on improving iPSC efficiency and since the first iPSC publication, many papers have reported several other genes which enhance the efficiency of iPSC generation.
Inclusion of Utf1, another TF involved in ESC pluripotency, together with the inhibition of p53, increases iPSC generation by 200-fold [47]. Similarly, other factors (like the SV40 large T antigen, SV40LT; the telomerase reverse transcriptase, TERT) and microRNAs (miRNAs) controlling cell proliferation, senescence and apoptosis also affects the efficiency and the speed of reprogramming [48-52]. Other studies have reported important roles for Sall4 [53], Esrrb (which can replace Klf4] [54] and Tbx3 (which improves the germline contribution) [55].
The starting cell, used for reprogramming, is a key parameter that influences the kinetics, the efficiency and the quality of the iPSCs. Fibroblasts are the most commonly used somatic cells because they can be easily isolated. In mouse studies, embryonic fibroblasts (MEFs) are commonly used as iPSCs can be generated in 10-12 days; MEF-derived iPSC generation is therefore recommended for studies aimed at understanding the mechanisms underlying iPSC generation, as well as the TFs and the chemicals that may enhance this process.
To generate iPSCs from human foreskin fibroblasts (HFFs), three weeks are required and the efficiency is 100 fold less compared with human primary keratinocytes, in which reprogramming also occurs faster [56]. When using CD133+ cord blood cells, iPSCs can be produced by overexpression of only Oct4 and Sox2. As cord blood banks exist, it is believed that this cell source may be useful to make an iPSC bank representing a wide panel of haplotypes for regenerative medicine [57].
Another crucial parameter is the differentiation status; Hematopoietic stem cells and progenitors have a higher efficiency of reprogramming than terminally differentiated B- and T-lymphocytes [58]. Similarly, Sox2+ neural progenitor cells form iPSCs just by forced overexpression of Oct4 [59]. Many other cell types, such as adipose stem cells [60], dental pulp cells [61], oral mucosa cells [62] and peripheral blood cells [63] can also be used to generate iPSCs.
iPSCs from different origins have a similar, if not identical, gene expression profile in their pluripotent state. However, it has become clear that some genomic regions are differentially methylated [64]; they retain an epigenetic memory of the cell of origin and this is reflected in their differentiation capacity. For example, iPSCs generated from blood poorly differentiated into neuronal cells but had a higher capacity to differentiate into hematopoietic cells [65].
The cell of origin to be used for iPSC generation, also has impact on safety issues; iPSC lines, generated from tail tip fibroblasts, have shown a higher propensity to form teratomas than lines obtained from stomach, hepatocyte or MEF, due to the persistence of undifferentiated cells even after iPSC differentiation [66].
The method of transgene delivery is a crucial factor in determining the efficiency but also the clinical relevance of iPSCs. Although initial reports were based on retroviral vectors, later publications described several other methods, which allow the generation of iPSCs. They can be divided into two main groups: integrative and non-integrative methods [67, 68]. Integrative methods are in general more efficient but they are less safe than the non-integrative methods, which are, however, inefficient.
When choosing the strategy of reprogramming, it is important to consider the aim of the study; integrative methods, the most efficient ones, should be used for elucidating mechanisms underlying iPSC generation, and TFs and chemicals that may enhance this process, while, non-integrative methods will be required to generate clinical-grade iPSCs.
Mouse and human iPSCs were initially produced by transduction of Moloney murine leukemia virus (MMLV)-derived retroviral vectors. Vectors, based on this system, allow cargoes of up to 8Kb fragments, can efficiently infect (although only dividing cells) and are generally silenced in pluripotent cells [69].
Lentiviral vectors, derived from HIV, have also been used. Differently from the retroviral vectors, the latter have a higher cloning capacity (up to 10Kb of DNA) and can infect both dividing and non-dividing cells. However, transgenes introduced using lentiviral vectors are less-silenced and this can result in a more laborious identification of bona fide iPSC clones (having the transgenes silenced). The lentiviral vector system allowed the Tet-inducible expression of the transgenes in a tightly controlled way [70]. Subsequently, polycistronic lentiviral vectors, having the OSKM cDNA under the control of a unique promoter were used [71]. This was possible by including in between the different cDNAs, the 2A self-deleting peptide. This permits the continuous translation of downstream cDNA after the release of the previous protein [72]. In general, viral vector-based methods are quite efficient and reproducible (>0.1% in mouse cells, <0.01 in human cells). However, clones generated by viral delivery are not clinically safe. The transgenes may be reactivated during iPSC differentiation; moreover long terminal repeats (LTR) may activate proto-oncogenes increasing their tumorigenicity [28, 73].
Another possible strategy for iPSC generation is the transient delivery of OSKM by Piggyback (PB) transposon [74]. This system consists of a donor vector, containing the cassette (OSKM), flanked by a 5’ and a 3’ inverted repeat, and a helper plasmid, expressing the PB transposase. When cotransfected, the cassette of the donor plasmid is pasted into the TTAA sequences present in the genome, but can be remobilized after the reprogramming [75, 76]. The PB transposon-mediated generation of iPSCs occurs with high efficiency and, among the integrative methods, this is the only one that allows a precise deletion of the cassette. However, alterations at the integration sites were found; therefore, sequences at the integrations sites must be verified.
Adenoviral vectors do not integrate into the host genome and can, thus, be used for making iPSCs [77, 78]. Adenoviral vectors can carry up to 36kB and can infect both dividing and non-dividing cells. However, the efficiency of iPSC generation is extremely low (0.002 to 0.0001%), probably because the premature dilution of adenoviral vectors during cell replication.
A more efficient alternative has been reported by Fusaki and colleagues [79], using F-deficient Sendai viral vectors. Sendai viruses are minus strand RNA virus, which replicate their genome in the host cytoplasm. Because these viral vectors replicate ubiquitously, their efficiency of reprogramming is similar to retroviral vectors. However, to obtain viral vector-free iPSCs, elimination of the vector using temperature sensitive mutant or antiviral compounds is required.
OriP/Epstain-Barr nuclear antigen-1-based (OriP/EBNA1) vectors can be transfected into host cells and maintained stably episomically (because they replicate during cell divisions through their oriP element) using a drug in the culture medium [80]. Yu and colleagues [81] used the combination of three OriP/EBNA1 vectors (having a combination of 10 reprogramming factors) to generate iPSCs from HFF. By removing the drug selection, episomal vectors are eliminated from proliferating iPSCs.
Another alternative are the minicircle vectors, that differently from the above vectors, are non-replicative [82]. These vectors have a better transfection efficiency than OriP/EBNA1, due to their reduced length (they lack the bacterial origin of replication and the antibiotic resistance gene). However, both strategies have a three-fold lower efficiency (<0.001%) than retroviral vector-based reprogramming.
Previous studies have shown that proteins can be directly delivered into cells by fusing them with peptides [83], which mediates their transduction, such as poly-arginine or the HIV transactivator of transcription (TAT). Zhou et al. [84] produced recombinant OSKM proteins fused with poly-arginine in
Similarly,
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t||
Viral | \n\t\t\tRetrovirus | \n\t\t\t+ | \n\t\t\t4X | \n\t\t
Viral | \n\t\t\tLentivirus | \n\t\t\t+ | \n\t\t\t3X | \n\t\t
Viral | \n\t\t\tAdenovirus | \n\t\t\t- | \n\t\t\t1X | \n\t\t
Viral | \n\t\t\tSendai Virus | \n\t\t\t- | \n\t\t\t4X | \n\t\t
DNA | \n\t\t\tTransposon | \n\t\t\t- | \n\t\t\t2X | \n\t\t
DNA | \n\t\t\tMinicircle | \n\t\t\t- | \n\t\t\tX | \n\t\t
DNA | \n\t\t\tEpisomal plasmid | \n\t\t\t- | \n\t\t\tX | \n\t\t
RNA | \n\t\t\tRecombinant RNA | \n\t\t\t- | \n\t\t\t3X | \n\t\t
PROTEIN | \n\t\t\tRecombinant protein | \n\t\t\t- | \n\t\t\tX | \n\t\t
Comparison of different strategies for iPSC generation
4x= >0.1%; 3X= <0.1%; 2X= <0.01%;1X= <0.001%
iPSCs were reproducibly derived from most, if not all, somatic tissues; however the efficiency reported is always less than 1%. It is the consensus of scientific community, that many more than 1% of the transfected/transduced cells start the reprogramming process. Using a live cell imaging approach, it was demonstrated [87] that almost all the transduced cells undergo symmetric divisions within 48 hours, retaining a fibroblast-morphology. At later stages, reprogramming cells undergo asymmetric divisions: one descendant becomes an iPSC while the other one undegoes cell death. Still unknown, stochastic and clonal events appear to control this process at later stages; in fact most of the cells do not complete the initiated process. Several studies have demonstrated key roles for demethylation [88], telomerase length [89] and mesenchymal to epithelial transition [90], during the reprogramming. A better understanding, especially of the later stochastic mechanisms, is still needed to fully understand and improve the efficiency of iPSC technology [91].
Another important question has been whether or not ESCs and iPSCs are similar and if not, whether differences are functionally important for their application. Conclusions from different studies are conflicting. Several papers have reported that there are remarkable differences in gene expression and DNA methylation [92, 93], while other studies, which included a large number of ESC and iPSC lines, concluded that it is quite difficult to distinguish between ESCs and iPSCs [94-96]. Considering that there are differences among different ESC lines [97], it is now believed that iPSCs clones have a higher variability than ESCs but that at least some iPSC clones are indistinguishable from ESCs.
Furthermore, the recent work of Young and colleagues [98] demonstrated that most of the genetic variability in between different iPSC clones is already present in the starting cell line and is thus not caused by the reprogramming process.
Interestingly, in the last five years, several studies have clearly demonstrated the potential of iPSC technology in regenerative medicine. Hanna et al [99] generated iPSCs from a humanized model of sickle cell anemia. After correcting the hemoglobin gene, by gene targeting, iPSCs were able to generate hematopoietic stem cells and to rescue the disease. Similarly, the potential of iPSCs for cell therapy was demonstrated for macular degeneration [100], Parkinson’s disease [101], platelet deficiencies [102] and spinal cord injury [103, 104].
iPSCs derived from patients with specific diseases have been used for studying the mechanisms involved in these diseases and for drug screening [105, 106].
As a result of the success with reprogramming of somatic cells to a pluripotency-state, lineage reprogramming (trans-differentiation) between different somatic cell types has also become a burgeoning field of research (see next section).
In conclusion, iPSC technology will, in the near future, have a drastic impact on science, regenerative medicine and business. Precise selection of “clean” clones, through the evaluation of their genomic and epigenetic integrity, as well as their gene expression profile, will be crucial for downstream applications. Despite these remaining hurdles, it is believed that clinical applications for iPSCs are not far off.
The discovery of iPSCs, together with previous experiments involving SCNT and cell fusion, clearly showed that differentiation is a reversible process and that cells are more ‘plastic’ than previously believed. Therefore, a new field, called lineage reprogramming, emerged rapidly in the last five years. Recent attempts have demonstrated that, the forced overexpression of TFs can also convert one cell type to another of the same or of other somatic germ layers. Lineage reprogramming depends on the capacity of certain TFs to overcome the existing epigenetic barriers and to rapidly initiate the new identity-specific gene network [110-113].
Examples of direct lineage conversion were described already in 1986; Davis, Lassar et al. [114, 115] converted different fibroblast lines into myogenic cells by overexpression of MyoD, a basic helix-loop-helix transcription factor, in combination with the demethylating agent, 5-azacytidine. Subsequent studies confirmed that myogenic conversion, as shown by presence of desmin and myosin heavy chain, could be achieved
A similar transdifferantiation was also seen in the blood system. The deletion of Pax5 in pro-B cells resulted in their switch into the T-cell lineage [118, 119]. Later on, the same group investigated this transdifferentiation more extensively; mature B cells were isolated from Pax5 knockout mice and transplanted back into a lymphocyte deficient recipient. Surprisingly, they could detect in the reconstituted mice donor pro B cells, which then gradually converted into T cells [120]. This demonstrated that lost of Pax5 led to a T cell phenotype through de-differentiation rather than direct transdifferentiation. Another example of direct conversion came from the work done by Graf and colleagues [121]; overexpression of C/EBP
The above examples describe experimental conversions but there were also cases in which this conversion occurs naturally. Jarriault et al. [122], demonstrated that the epithelial rectal cell ‘Y’, migrates anterodorsally from the rectum to become a ‘PDA’ motor neuron. This conversion from Y to PDA is not direct but occurs through a de-differentiation state, in which the initial (Y-cell) and the final (PDA-cell) identity are not present [123]. In this section, we will describe the relevant cell types, recently, obtained by lineage reprogramming.
Seale and colleagues have recently found that Myf5+ muscle precursors can convert into brown fat cells
Human dermal fibroblasts were converted into multipotent blood progenitors by just Oct4 overexpression [126] in combination with treatment with a hematopoietic permissive medium, containing growth factors and cytokines. Oct4 is a key TF for pluripotency but it is not expressed in the hematopoieic system [127]; probably, Oct4, in this case of lineage reprogramming, is mimicking the effect of Oct1 and Oct2, two other members of Pou family of TFs expressed in lymphoid development [128]. The induced progenitors express CD45 and express adult globin protein (unlike hematopoietic cells derived from human ESCs and iPSCs). Multipotent blood progenitors have myeloid, erythroid and megakaryocytic but not lymphoid potential, as shown by transplantation experiments.
The forced overexpression of TFs involved in cardiac development (Tbx5, Mef2c and Gata4) converts mouse cardiac and dermal fibroblasts into cardiomyocyte-like cells, termed induced cardiomyocyte (iCMs) [129]. Around 20% of the cells appear to be ‘converted’ in three days as measured by the expression of alpha-myosin heavy chain (αMHC), although one month is required for their complete maturation, which resulted in spontaneous beating capacity. Transplantation of iCMs, the day after the viral transduction, in injured hearts results in their engraftment and differentiation
The lineage reprogramming into β-cells is of particular interest, considering the potential for the treatment of diabetes. Zhou et al., [132] were able to
More recently, mouse fibroblasts were converted into hepatocyte-like cells by overexpressing Hnf4α, FoxA1, FoxA2 and FoxA3 [133] or by Gata4, Hnf1α, Foxa3 together with p19Arf inactivation [134]. The reprogrammed cells were termed induced hepatocytes (iHeps) and had a gene expression profile and features (albumin production and cytochrome P450 activity), which closely resemble mature hepatocyte. iHeps
The conversion into neuronal types is, probably, the one that received more attention in the field of lineage reprogramming. The increasing attention is due to their possible application for the treatment of diseases involving the nervous system.
In 2010, Vierbuchen et al. [135] were the first to describe how overexpression of Ascl1, Mytl1 and Bm2 (also known as Pou3f2, again a member of Pou family) can convert embryonic and tail-tip fibroblasts into a mixed populations of induced neurons (iNs). iNs generate functional synapses with mouse cortical neurons and have action potentials; the detailed electrophysiological analysis showed that iNs contains mainly cells with features of glutamatergic neurons (with just a small percentage of GABAergic neurons). Remarkably, the addition of NeuroD1 to the above set of genes was necessary to achieve the same conversion in human cells [136]. The enriched cocktail of factors was able not only convert fibroblasts but also mouse hepatocyte into iNs [137].
Several groups, differently, converted fibroblasts into induced neural stem cells (iNSCs), that differently from the previous examples, can still self-renew and differentiate into different neuronal subtypes (multipotent). Different cocktail of factors and inductive media have been used to obtain multipotent neuronal stem cells from human and mouse fibroblasts: the group of Scholer [138] used Sox2, Klf4, c-Myc, together with Tcf3 and Brn4 (also known as Pou3f4); our group [139] by adding Zic3 to Oct4, Sox2 and Klf4; Ring et al. [140], by just overexpressing Sox2.
Different laboratories focused on a more direct conversion into specific neuronal subtypes, with a particular interest on neuronal cell types affected in neurodegenerative diseases. Two groups have been able to convert mouse and human fibroblasts into induced Dopaminergic Neurons (iDAs), the subtype affected in Parkinson’s disease. The first laboratory [141] achieved this by adding FoxA2 and Lmx1a to Ascl1, Mytl1 and Bm2; the second [142] by overexpressing Ascl1, Lmx1a and Nurr1 (also known as Nr4a2). iDA cells, upon transplantation in mice, were capable to integrate into the host neuronal circuitry and express markers typical for mature dopaminergic neurons.
Lineage conversion was also achieved into spinal motor neurons, the subtypes involved in amyotrophic lateral sclerosis and spinal muscular atrophy. Conversion into induced Motor Neurons (iMNs) was achieved for both mouse and human fibroblasts; mouse embryonic fibroblasts were converted with Ascl1, Brn2, Mytl1, Lhx3, Ngn2, Isl1 and Hb9 whereas human cells also required NeuroD1 [143]. iMNs displayed markers, electrophysiological features and gene expression profile, which strongly resemble motor neurons. Moreover, iMNs engrafted into the developing chick spinal cord, forming axonal and dentritic projections toward the adjacent musculature.
Of note, Qiang et al [144] demonstrated that lineage reprogramming is also useful for drug screening and disease modeling. iNs, again with glutamatergic features, were induced by overexpressing Ascl1, Bm2, Mytl1 together with Zic1 and Olig2. iNs were produced from both healthy donors and Alzheimer’s patients. iNs produced from patients displayed the typical accumulation of beta amyloid peptides (Aβ40 and Aβ42). Combining lineage reprogramming with gene-targeting technology, similar cells could also be used for autologous transplantation.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
(m) Β-Cells | \n\t\t\tMacrophage-like cells | \n\t\t\tC/EBPα or β, PU.1 (121) | \n\t\t
(m/h) dermal fibroblasts, myoblasts | \n\t\t\tBrown-fat cells | \n\t\t\tC/EBPα and PRDM16 (125) | \n\t\t
(m) embryonic fibroblasts | \n\t\t\tMyoblasts | \n\t\t\tMyoD (114, 115) | \n\t\t
(h) dermal fibroblasts | \n\t\t\tMultipotent blood progenitors | \n\t\t\tOct4 (126) | \n\t\t
(m) cardiac and tail tip fibroblasts | \n\t\t\tCardiomyocytes | \n\t\t\tTbx5, Mef2c, Gata4 ± Hand2 (129) (131) | \n\t\t
(m) embryonic fibroblasts | \n\t\t\tCardiomyocytes | \n\t\t\tOct4, Sox2, Klf4 and cMyc (145) | \n\t\t
(m) exocrine cells | \n\t\t\tβ-like cells | \n\t\t\tNgn3, Pdx1 and MafA (132) | \n\t\t
(m) embryonic and dermal fibroblasts | \n\t\t\tHepatocyte-like cells | \n\t\t\tHnf4α, FoxA1, FoxA2 and FoxA3 (133) | \n\t\t
(m) embryonic and tail tip fibroblasts | \n\t\t\tHepatocyte-like cells | \n\t\t\tGata4, Hnf1α, Foxa3 and p19Arf KD (134) | \n\t\t
(m) embryonic fibroblasts | \n\t\t\tNeural progenitor cells | \n\t\t\tOct4, Sox2, Klf4 and cMyc (146) | \n\t\t
(m/h) fibroblasts | \n\t\t\tNeural progenitor cells | \n\t\t\tSox2, Klf4, c-Myc,Tcf3 and Brn4 (138) | \n\t\t
(h) fibroblasts | \n\t\t\tNeural progenitor cells | \n\t\t\tOct4, Sox2, Klf4 and Zic3 (139) | \n\t\t
(m) embryonic and (h) fetal fibroblasts | \n\t\t\tNeural progenitor cells | \n\t\t\tSox2 (140) | \n\t\t
(m) embryonic and (h) fetal, postnatal and dermal fibroblasts | \n\t\t\tNeurons | \n\t\t\tAscl1, Mytl1, Bm2 and NeuroD1 (135) (136) | \n\t\t
(m) tail and (h) embryonic fibroblasts | \n\t\t\tDopaminergic neurons | \n\t\t\tAscl1, Lmx1a and Nurr1 (142) | \n\t\t
(h) embryonic and fetal lung fibroblasts | \n\t\t\tDopaminergic neurons | \n\t\t\tAscl1, Mytl1, Bm2, Lmx1a and FoxA2 (141) | \n\t\t
(h) skin fibroblasts | \n\t\t\tGlutamatergic neurons | \n\t\t\tAscl1, Bm2, Mytl1, Zic1 and Olig2 (144) | \n\t\t
(m/h) embryonic fibroblasts | \n\t\t\tMotor neurons | \n\t\t\tAscl1, Brn2, Mytl1, Lhx3, Ngn2, Isl1, Hb9 and NeuroD1 (143) | \n\t\t
Examples of lineage conversion. (m)= mouse (h) = human
Most of the examples, given in the previous section, describe the direct conversion from one cell type to another, in which the reprogramming is achieved without any intermediate state. However, other reports clearly demonstrated the possibility to achieve similar results, by using an alternative strategy, in which lineage conversion is indirect. Indirect conversion is achieved passing through a limited de-differentiation state by overexpressing Yamanaka factors for a shorter time. Like for the direct conversion, the indirect conversion is strongly dependent on the specific culture medium (growth factors and cytokines) given during the reprogramming phase.
The laboratory of Sheng Ding, at the Gladstone Institute of San Francisco, was the first to describe the possibility of lineage reprogramming through an indirect strategy. Short temporal overexpression of the Yamanaka factors induced a partial dedifferentiatied state, that allowed the subsequent conversion into cardiomyocytes-like cells by applying extracellular factors [145]. OSKM factors were overexpressed for six days in a medium free of signals necessary for pluripotency (i.e. leukemia inhibitory factor). After this short priming phase, cells were then cultured in media promoting cardiogenesis, i.e. cointaining BMP4. Three day after the cardiac induction, the expression of Nkx2.5, Gata4 and Flk1 (mid-stage markers of cardiac developments) could be detected. The further development into more mature cardiomyocytes, showing sarcomeric structures and cardiac features (expression of cardiac markers and cell-cell interaction) required at least two more days.
Interestingly, the authors also demonstrated that this indirect lineage conversion does not pass through a pluripotency-state, i.e. ESC/iPSC culture media in the induction phase drastically decrease the efficiency of conversion;
Both direct and indirect lineage conversions have pros and cons. The direct conversion, as in case of SCNT or cell fusions, occurs in hours-days. Induced cells are unipotent, are produced with a high efficiency, without the requirement of cell proliferation and with a lower risk for teratoma. The indirect strategy requires days-weeks and produces cells, which can be unipotent or multipotent. Cells induced by this strategy can be expanded but have a moderate risk for teratoma.
Reprogramming to the pluripotency-state occurs via a gradual and genome-wide de-differentiation, involving a first phase where epigenetic marks of differentiation are erased and a second phase in which the epigenetic marks of pluripotency are established to initiate the endogenous pluripotency-network. In lineage conversion, specific TFs are able to modulate cell fate in two different ways (direct or indirect), which does not involve a pluripotent-state and is associated with a lower tumor risk, still a major obstacle to achieve clinical applications with ESCs and iPSCs. In the direct conversion, ectopic TFs, involved in cell fate determination or maintenance during embryonic development, overcome the pre-existing epigenetic marks and generate a new state. In the indirect conversion, the TFs, which allow the reprogramming to the pluripotency-state, are temporally overerexpressed together with fate-specific signals to convert original cell type into a new state. Differently than iPSC technology, the efficiencies are much higher (even 20 % in some cases) and the kinetics of conversion are rapid (a few day to a week maximum, and not two weeks to a month, like for iPSC, see Table 3).
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
iPSC | \n\t\t\tLow | \n\t\t\tWeeks-Months | \n\t\t\tPluripotent | \n\t\t\tYes | \n\t\t\tHigh | \n\t\t\tRequired | \n\t\t
Direct conversion | \n\t\t\tHigh | \n\t\t\tHours-Days | \n\t\t\tUnipotent | \n\t\t\tNo | \n\t\t\tLow | \n\t\t\tNot required | \n\t\t
Indirect conversion | \n\t\t\tHigh | \n\t\t\tDays-Weeks | \n\t\t\tMulti/Unipotent | \n\t\t\tYes | \n\t\t\tModerate | \n\t\t\tRequired | \n\t\t
Comparison of different strategy of TF-based Reprogramming
As for iPSCs, many questions still remain unsolved in lineage conversion. It is not clear whether the new cell type, generated upon conversion, is a hybrid between the original and the new cell. It is intriguing that, in direct conversion, TFs erase partially or completely the previous epigenetic marks, without cell divisions (in which chromatin marks are lost) but it is totally unknown how this is possible. Remarkably, in both iPSCs and lineage conversion, efficiencies are lower with human cells, if compared with mouse. It is unknown whether this is due to the intrinsic karyotypic instability of mouse cells in culture or to molecular mechanisms.
Reprogramming to the pluripotency-state and lineage conversion are achieved through the forced expression of TFs. However, in the last decade, several reports have highlighted how culture medium per se can be responsible for (partial) reprogramming. Moreover, there is an increasing amout of evidences showing that small molecules, including epigenetic modifiers and signaling pathway inhibitors, enhance the efficiency and kinetics of reprogramming.
Epiblast stem cells (EpiSCs) are isolated from post-implantation embryos between E5.5-E7.5. EpiSCs are the post-implantation equivalent of ESCs; they still express Oct4, Nanog and Sox2 but express lower levels of Stella and Rex1 [147]. ESCs and EpiSCs have also different culture requirements and features. While ESC selfrenewal is LIF dependent, EpiSC proliferation requires bFGF and Activin signaling. EpiSC female lines, but not ESC lines, have one of the X chromosome inactive. Importantly, EpiSCs, differently from ESCs, do not have the ability to contribute to chimeras
In 2009, Bao et al. [148] demonstrated that established EpiSC lines could de-differentiate/revert into an ESC-like state by culturing EpiSCs in ESC medium (cointaining LIF) for 2-5 weeks. Once ’reverted’ cells lost all the features of the original EpiSCs and acquired all ESC-characteristics ( X was reactivated, growth was LIF-dependent and cells were capable to contribute to chimeras). This report showed that the simple manipulation of culture medium can dedifferentiate EpiSCs to a more primitive ESC-state but this is not the only case reported in literature.
In 2004, Kanatsu-Shinohara et al. [149] descibed that mouse germline stem cells (GSCs) isolated from neonatal testis reverted occasionally into cells with ESC-like colonies morphology within 4-7 weeks if cultured in LIF, epidermal growth factor (EGF), glial cell line-derived neurotrophic factor (GDNF) and fibroblast growth factor 2 (FGF2). The reverted cells were named multipotent germ stem cells (mGSs); they expressed not only Oct4 (already present in GSCs) but also Nanog and Sox2 at ESC-level. Analysis on mGSs showed the loss of spermatogonial properties (although the erasure of the androgenic imprinting was not complete) and the gain of ESC features (teratoma formation and contribution to chimeras with germline transmission). However, despite their siimilarity to ESCs, mGSs were not able to form offspring, after tetraploid complementation. Unipotent germline stem cells, but this time from adult testis, were converted into germline-derived pluripotent stem cells (gPSs) by Ko and colleagues [150]. Reprogrammed cells, like in the above case, were higly similar to ESCs but again, they could not form live animals in tetraploid complementation assay. The reason for this is most likely the residual persistence of androgenetic imprinting. The possibility to reprogram a germline stem cell into a cell with pluripotent features, even without the capacity of forming chimeric animal, is interesting because it might allow autologous cell therapy without embryo-manipulation. Similar conversions with mouse cells were also described by other laboratories [151, 152].
In 2008, Conrad and colleagues [153], showed that cells derived from human testis can be converted into cells with human ESC-like features. Cells isolated from human testis were cultured in GDNF-containing medium for 4 days and then selected based on the expression of CD49f and further selection on laminin matrix in medium cointaining LIF. 3-4 weeks later colonies with ESC-morphology appeared; human adult GSCs (haGSCs), like human ESCs, expressed SSEA4, TRA 1-60, TRA 1-81 and generated EBs and teratomas. However, a later report [154] questioned the previous finding of Conrad, arguing whether haGSCs really expressed Oct4, Nanog and Sox2; moreover, microarray data comparison further showed that haGSCs are similar to fibroblasts-derived from human testic biopsies but not to hESCs.
These studies strongly suggest that stem/progenitor cells derived from testis can to some extent be converted, by long-term culture, to cells with ESC-like properties, without any reprogramming factors; however, converted cells differ significantly from ESCs. The propensity of GSCs to be converted to ESC-like cells may depend on their Oct4 expression. Although gonads are the only place where Oct4 is functionally expressed in adult healthy-rodents [127], many reports described the isolation of Oct4+ cells from rodents [155-169]. It remains to be determined whether culture mediated reprogramming is responsible for the Oct4 re-activation in such cell lines.
In 2002, our group [170] isolated multipotent adult progenitor cells (MAPCs) from rodent bone marrow (BM), upon prolonged culture at low density in a medium cointaining LIF, PDGF and EGF. Murine MAPCs differentiated
Moreover, specific culture media may also be responsible for the broader differentiation potential described for some adult stem cell types [175] and this should be more considered in stem cell research, especially when reaching clinical trials phases [176].
Small molecules are acquiring, on a daily basis, more relevance in the stem cell field because they can control protein functions selectively, reversibly and in a tunable way. Strikingly many reports have also shown how pathway inhibitors and epigenetic modifiers play a crucial role in the reprogramming process [177]. In 2010, the group of Ding reported that human primary somatic cells can be reprogrammed into human iPSCs with only Oct4 and a cocktail of small molecules [178].
Mouse (m)ESCs were first isolated more then three decades ago [179, 180]. mESCs have been derived and cultured in LIF and bone morphogenetic protein (BMP, contained in the serum) to inhibit their differentiation [181]. However, the efficiency of mESCs derivation was low in general and almost not possible from some mouse strains (like C57BL/6). More recently, several reports have now demonstrated that mESC culture in MEF or feeder-free are heterogeneous and fluctuates between a pre-implantation ESC and a post-implantation EpiSC-state [182, 183].
Ying and colleagues [184] demonstrated that mESCs can be maintained in an homogenous ground-state without the requirements of external stimuli, provided by growth factors and/or feeders. This achievement was possible by using two signaling modulators that regulate pathways involved in mESC differentiation:
Mesenchymal-to-epithelial transition (MET) is a reversible process which drives cells from a multipolar, spindle and motile mesenchymal shape to a planar and polarized epithelial shape. MET is an important process during embryo development but also in reprogramming; i.e. fibroblasts change shape towards an epithelial morphology at the early stage of iPSC generation. TGFβ pathway negatively regulates an epithelial phenotype. The block of TGFβ1-2-3 receptors, using
Cellular senescence is a pathway that negatively interferes with reprogramming. Expression of OSKM increases oxidative stress and DNA damage, inducing senescence.
Stem cells have a different metabolism if compared to differentiated cells [189]. Stem cells have a strong energetic and metabolic demand to meet their self-renewal and to do this, they mainly rely on glycolysis followed by fermentation of lactic acid in the cytosol. Differently, differentiated cells mainly rely on a low rate of glycolysis followed by oxidation of pyruvate in the mitochondria, which results in the production of ROS. Consistent with this,
The structure of eukaryotic genome is higly organized; genomic DNA is wrapped around structural proteines, called histones. DNA and histones, together, form the chromatin. Protein complexes are responsible for chromatin modifications. Histones then determine the transcriptional status; i.e. in an open and closed form. In somatic cells, chromatin is mainly in a closed conformation, while in pluripotent cells, chromatin is in an open conformation and it is dynamically associated with chromatin proteins. Obviously, during iPSC generation, the chromatin must change from a somatic to a pluripotent state. Therefore, many small molecules, which modulates chromatin have been described to enhance the efficiency of reprogramming and even to substitute for some of the reprogramming factors.
Pluripotent stem cells have, in general, a more demethylated DNA, in comparison with somatic cells; in fact,
G9a is an histone methyltransferase (HMTase), which induce silencing of Oct4, through methylation of H3K9.
Similarly,
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
PD0325901 | \n\t\t\tSignaling modulators | \n\t\t\tMEK inhibitor | \n\t\t
CHIR99021 | \n\t\t\tSignaling modulators | \n\t\t\tWNT/β-Catenin | \n\t\t
SB431542 | \n\t\t\tSignaling modulators | \n\t\t\tMET | \n\t\t
Vitamin C | \n\t\t\tSignaling modulators | \n\t\t\tCellular Senescence | \n\t\t
PS48 | \n\t\t\tSignaling modulators | \n\t\t\tGlycolysis | \n\t\t
5-aza, RG108 | \n\t\t\tEpigenetic modifiers | \n\t\t\tDNMT inhibitor | \n\t\t
BIX-01294 | \n\t\t\tEpigenetic modifiers | \n\t\t\tHMTase inhibitor | \n\t\t
Parnate | \n\t\t\tEpigenetic modifiers | \n\t\t\tLSD1 inhibitor | \n\t\t
TSA, SAHA, VPA | \n\t\t\tEpigenetic modifiers | \n\t\t\tHDAC inhibitor | \n\t\t
Small molecules in reprogramming
The importance and the impact on society of reprogramming has been recently recognised by the Nobel Assembly at the Karolinka Institute of Stockholm, which co-awarded John Gurdon and Shiniya Yamanaka with the Nobel Price in Medicine 2012. Their outstanding reports demonstrated that cellular fate is plastic and that differentiation is a reversible process. Epigenetic markers imposed by development can be erased through the multiple pathways to reprogramming. This means the epigenetic landscape as described by Waddington should be revised, as balls are capable of rolling back up and over the hill. The SCNT and the forced expression of TFs show that somatic cells can re-acquire all the features, lost upon their differentiation. Adult somatic cells can be redirected to the pluripotency-state or can be converted into cells of another lineage.
Although the precise mechanism via which the phenotype of all these cells can be changed remains to be fully elucidated, the iPSC technology is drastically changing and boosting the stem cell field; it allows one to obtain pluripotent stem cells for autologous therapy, avoiding the problems of immune rejection as well as the ethical issues related to the use of human embryo for scientific purposes. The possibility to also obtain precursors, with restricted differentiation potential, may be another alternative to reach the bedside, as it is likely associated with lower tumorigenicity. It is also clear that culture conditions have such a significant effect on cell fate, not only during reprogramming but also in establishing the potential of different adult stem cells, that this should be kept in mind when comparing studies across laboratories, and definitely when contemplating clinical trials with cultured stem cells.
Aneurysmal subarachnoid hemorrhage (SAH) is a complex condition with an intricate and poorly understood pathophysiology. Increasing evidence strongly suggests that neuroinflammation plays a critical role after SAH, but conventional anti-inflammatory treatments have failed to improve clinical outcome [1]. Clinical research on SAH has mainly focused on delayed cerebral ischemia (DCI); however, DCI does not encompass the entire spectrum of pathological and clinical manifestations of SAH [2, 3, 4]. Although cerebral infarction is associated with poor clinical outcome and death after SAH, a significant proportion of SAH patients without cerebral infarction suffer from cognitive deficits and mood disorders and a reduced ability for activities of daily living and working, even in the long term [5, 6]. The absence of a close correlation between DCI and functional recovery indicates an ongoing pathophysiological process has been overlooked in SAH. The failure of the recent major NEWTON 2 clinical trial, of sustained intraventricular release of nimodipine, is the latest in a series of unsuccessful phase 3 randomized controlled trials (RCTs) to improve clinical outcome after SAH and further reinforces the need to identify novel therapeutic strategies [7, 8].
\nNutrition is essential to human health, and appropriate nutritional support is currently considered a standard of care for critically ill patients. Malnutrition—including depletion of essential micronutrients—frequently occurs among critically ill patients and is associated with an increased risk of morbimortality [9]. However, the clinical relevance of key nutrient deficiencies in acute neurological illnesses has not been thoroughly investigated. EPA and DHA are essential constituents of endothelial and neuronal membranes, respectively, and also the precursors of key mediators involved in resolution of inflammation and endogenous neuroprotection [10, 11]. Although massive loss of brain DHA in SAH patients was first reported over 15 years ago, the pathological significance of this process and the role of inflammation resolution following SAH have largely been ignored [11, 12]. Therapeutic interventions aimed at stimulating inflammation resolution and recovering the homeostasis of the brain and other vital organs after SAH could improve patients’ functional outcome [13].
\nThis chapter provides an overview of the potentially harmful consequences of selective deficiency of omega-3 FAs on brain structure and function in SAH patients. Moreover, given the possible clinical relevance to SAH and the growth and rupture of intracranial aneurysms (IAs), we provide a detailed discussion of recent findings on the role of omega-3 FAs in resolution of inflammation, with a focus on brain homeostasis.
\nRemarkable progress in our understanding of the pathophysiology of acute inflammation has been achieved through basic science over the last 20 years. Resolution of acute inflammation is now considered to be an active biochemical process that is required to enable tissues to restore normal structure and function following an injury [14]. Interference with the resolution phase of acute inflammation may result in necrosis, chronic inflammation, fibrosis, and organ dysfunction. The resolution process is triggered at the beginning of inflammation by a temporal switch in lipid mediator classes, which is induced by cross talk between cells of the innate immune system and other cells in the inflammatory microenvironment [11].
\nA diverse range of biologically active pro-resolving and anti-inflammatory mediators are synthetized by complex pathways that involve several enzymes, including cyclooxygenase 2 (COX-2), cytochrome P450s and several lipoxygenases (LOX). The majority of these endogenous mediators are derived from the long-chain omega-3 fatty acids (FAs) EPA and DHA and are members of the specialized pro-resolving mediator (SPM) superfamily [15]. SPMs represent an essential biochemical interface between inflammation and tissue repair and regeneration. The resolution of inflammation is a highly orchestrated adaptive process that depends on both the availability of SPMs precursors and the efficiency of the related biosynthetic pathways.
\nEach endogenous lipid mediator is structurally distinct and possesses specific biological functions which have been extensively studied in diverse experimental models. EPA is the precursor of the E-series resolvins (RvEs), which contains four main mediators (RvE1-RvE3 and 18-HEPE). DHA is the precursor of the D-series resolvins (RvDs), which contains six mediators (RvD1-RvD6), as well as the protectins (PD1-PDX) and the maresins (MaR1-MaR2); DHA derivatives are also known as docosanoids [15].
\nSPMs are active at pico-nanogram ranges and exert pleiotropic actions at the inflammatory microenvironment. SPMs stimulate the clearance of bacteria, dead cells, and debris that is required during tissue repair. SPMs also reduce leukocyte transendothelial migration, platelet activation, and production of inflammatory cytokines, thus providing multi-organ protection. The maresins (macrophage mediators in resolving inflammation) exert potent phagocyte-directed actions that include phenotypic conversion of proinflammatory macrophages into macrophages that suppress inflammation and promote tissue regeneration [16]. Collectively, SPMs actively promote resolution of inflammation and recovery of tissue homeostasis [15]. Interestingly, resolution of systemic inflammation appears to have its counterpart in the CNS represented by different DHA-derived endogenous mediators (see Section 5.1).
\nThe biosynthetic pathways that generate SPMs are clinically relevant and have been comprehensively studied [15, 16]. Drugs that inactivate the enzymes involved in SPM biosynthesis, such as selective COX-2 inhibitors and certain LOX inhibitors, delay the return to homeostasis and are considered resolution antagonists. Importantly, selective COX-2 inhibitors were synthesized before the identification of inflammation resolution pathways and are currently widely used as anti-inflammatory agents. Aspirin and statins also modify COX-2 by acetylation and S-nitrosylation, respectively, which results in generation of longer-acting SPM R-epimers. Thus, aspirin and statins are resolution agonists [15, 16].
\nIncorporation and transport of omega-3 FAs have been comprehensively described; here, we focus on the clinically relevant aspects [10, 17, 18]. Several studies have consistently shown that in vivo conversion of alpha linolenic acid (ALA), the short-chain omega-3 FAs from vegetable origin, to its bioactive long-chain derivatives (EPA and DHA) is very low in humans. In addition, the metabolism of omega-6 and omega-3 FAs is tightly linked, and thus a high dietary intake of omega-6 FAs further reduce the conversion of ALA to EPA and DHA and their biological effects. The body has also a limited capacity to store long-chain omega-3 FAs; only very small amounts of EPA and DHA are present in adipose tissue, and the brain retains DHA for its own function. Thus, providing preformed EPA and DHA is the most efficient method of increasing the concentrations of EPA and DHA in plasma and tissues.
\nEPA and DHA are incorporated into different blood lipid fractions after absorption by the gastrointestinal tract or after release from intravenously infused fish oil-based lipid emulsions (FOLE). These lipid fractions reflect the diverse means by which FAs are transported in the circulation and execute their physiological functions. The fractions incorporated in the phospholipid coat of plasma lipoproteins and plasma nonesterified FAs (NEFAs) are considered transport pools. Notably, the NEFA pool seems to be the main DHA plasma fraction that supplies the brain. The NEFA pool also represents a direct source of FAs to cells for generation of SPMs, as this pool readily transfers to inflammatory tissue via edema formation [19]. The FAs fraction incorporated in peripheral blood mononuclear cells (PBMCs) represents a functional pool due to the crucial roles of PBMCs in inflammation.
\nThe EPA and DHA content of red blood cells (RBCs) membrane which can be quantified by a specific and standardized analytical procedure—the HS-Omega-3 Index® methodology—reliably reflects the omega-3 FAs content of several tissues [20]. This omega-3 index has been increasingly utilized as a surrogate marker of omega-3 status. Long-term intake of EPA and DHA is the main predictor of the omega-3 index, but other factors influence its variability. Acute supplementation of omega-3 FAs does not modify the omega-3 index, as expected given the long lifetime of RBCs (100–120 days). In terms of clinical relevance, strong inverse correlations have been observed between the omega-3 index and cardiovascular morbimortality, particularly sudden cardiac death, as well as depression [21, 22, 23].
\nMicrovascular inflammation is an early event in the pathogenesis of atherosclerosis and other inflammatory conditions and is inextricably linked to microthrombosis [24]. Eicosanoid metabolism and leukocyte-endothelial interactions are interrelated processes and in turn are major drivers of thromboinflammation [25, 26]. Inflammation stimulates eicosanoid synthesis and expression of cell-surface adhesion molecules through upregulation of the nuclear factor kappa B (NF-kB), a master transcription factor necessarily involved in the inflammatory response.
\nMost eicosanoids derived from the long-chain omega-6 FAs arachidonic acid (ARA), including prostaglandins, leukotrienes, and thromboxanes, are potent vasoconstrictors, platelet activators, and leukocyte chemotactic factors. Moreover, the expression of cell-surface adhesion molecules on endothelial and inflammatory cells is essential for leukocyte-endothelial interactions; rolling and adhesion on vascular surfaces are the first step in the recruitment of circulating leukocytes or platelets to sites of thromboinflammation [27].
\nEPA incorporated in the membrane phospholipids of inflammatory cells can modulate eicosanoid metabolism by replacing ARA as an eicosanoid precursor [25]. EPA-derived eicosanoids are significantly less potent than those derived from ARA, and nonesterified EPA can also directly inhibit the production of eicosanoids from ARA. In addition, EPA has been shown to decrease the expression of several cell-surface adhesion molecules on inflammatory cells. EPA appears to elicit these pleiotropic effects by modulating the activity of the NF-kB.
\nAdditionally, recent mechanistic studies have shown that minor changes in the EPA content of endothelial membranes may markedly alter the biophysical properties of the membrane [28]. Furthermore, changes in membrane fluidity, thickness, and deformability induced by modifications to lipid dynamics and/or structural organization can profoundly impact endothelial function [29]. Given the intimate association between brain capillary pericytes and endothelial cells, it would not be surprising if EPA also incorporates into pericyte cell membranes and potentiates the function of these cells as regulators of brain homeostasis [30, 31].
\nDHA is widely distributed throughout the human body in membrane phospholipids and is particularly abundant in neural tissues such as the brain and retina [10]. DHA represents 30–40% of the fatty acid content of the gray matter in the cortex and is absorbed into the brain by a specific transporter that is found in the endothelium of the blood-brain barrier (BBB) microvasculature [32, 33]. The functional significance of selective enrichment of DHA in neural tissues has been actively researched over the last few decades. DHA possesses unique biophysical and biochemical characteristics that make it particularly suitable for brain and retinal membranes. DHA has been highly conserved during evolution and is present throughout the entire spectrum of living organisms [34]. DHA has even been suggested to be a major determinant for evolution of the modern hominid brain due to its unique encephalization potential [35].
\nDHA is an essential component of neuronal membrane architecture and composition and promotes selective accumulation of phosphatidylserine (PS), a crucial phospholipid involved in intracellular signaling [36]. PS participates in the signaling events of several key enzymes, including protein kinase C, Raf-1 kinase, and Akt, which play essential roles in cell proliferation, differentiation, and survival. Thus, DHA significantly modulates the activity of essential cellular kinases in neuronal cells.
\nIn addition to its function as a unique building block of cell membranes, DHA is also a precursor for docosanoids and other bioactive endogenous derivatives in the neural tissue [37]. The number of recently identified DHA derivatives in neural tissue is increasingly growing and includes neuroprotectin D1 (NPD1), synaptamide, endocannabinoid epoxides, and elovanoids [38, 39, 40]. Collectively, the potent bioactive properties of these DHA derivatives contribute to preservation of normal neuronal function, tissue homeostasis, and neuronal survival [37, 38, 39, 40, 41]. In addition, the DHA derivatives exert a range of potent neuroprotective properties that include inhibition of proinflammatory gene expression and leukocyte infiltration. A striking hallmark of the DHA derivatives is their ability to potentiate microglial polarization from a proinflammatory phenotype to a surveillance-repair state and reduce NF-kB-mediated expression of inflammatory cytokines in the brain. Moreover, DHA derivatives contribute to BBB integrity and are neurogenic and synaptogenic [38, 42]. Thus, the DHA derivatives seem to be key mediators of the resolution of inflammation and recovery of homeostasis in the CNS microenvironment.
\nThe concept of neurovascular unit emphasizes the intimate relationship between the brain and its vessels, particularly the coupling between neural activity and cerebral blood flow [43]. Although the role of DHA neurolipidomics in neurovascular coupling appears to be underestimated, substantial experimental evidence suggests that the morphologic and functional integrity of the neurovascular unit largely depends on high DHA enrichment [37, 40, 43]. Moreover, the potential role of EPA in microvascular function further supports the evolutionary importance of these essential nutrients to maintain efficient functional couplings between neural and vascular networks [28, 29]. A functional neurovascular unit may be crucial not only for neurovascular coupling but also for BBB integrity and neurogenesis.
\nA regular dietary supply of DHA is required to preserve normal brain and retinal function. Under physiologic conditions, the net DHA incorporation rate for the entire human brain is very low and equivalent to the net rate of DHA consumption by the brain (3.8 ± 1.7 mg/day) [44]. However, loss of DHA in pathological states or due to nutritional deficiency of omega-3 FAs may severely impair neurovascular integrity and have far-reaching implications on normal brain function [36].
\nTo date, three clinical studies have examined the loss of DHA from the brain after SAH. Pilitsis et al. conducted the first observational study to analyze free fatty acid (FFA) concentrations in cerebrospinal fluid (CSF) [12]. The concentrations of ARA, DHA, linoleic acid, myristic acid, oleic acid, and palmitic acid were measured over the first 14 days following SAH in 20 patients. A cohort of 73 patients with no evidence of acute neurological disease served as the control group. Compared to control patients, the concentrations of all FFAs tested were significantly elevated in CSF during the first 2 days after SAH, with a significant secondary increase in FAA concentrations at 8–10 days. The concentrations of DHA exhibited a biphasic increase and remained significantly elevated (200–600%) throughout the first 14 days after SAH.
\nIncreased levels of free DHA in CSF after SAH are likely to be the result of the cleavage of DHA from membrane phospholipids by either direct structural damage or an increase in phospholipase A2 activity in response to neuroinflammation. DHA can also be readily oxidized due to its high degree of unsaturation and excessive generation of free radicals following SAH [45]. Such nonenzymatic oxidation of DHA generates F4-neuroprostanes (F4-NPs), which represent a lipid marker of oxidative stress in the CNS. Two clinical studies confirmed that the concentrations of F4-NPs in CSF significantly increased within the first 24 hours following SAH compared to control patients [46, 47]. Hsieh et al. also showed the concentrations of F4-NPs in CSF remained significantly elevated throughout the first 10 days after SAH and suggested a positive correlation exists between F4-NP concentrations and clinical outcome at 3 months after SAH. Despite the limited number of patients analyzed, these studies provided valuable evidence that substantial loss of brain DHA occurs after SAH.
\nMoreover, it is highly likely that SAH may increase metabolic consumption of DHA though increased generation of neuroprotective derivatives. This potential additional source of DHA loss has not yet been evaluated but could be significant. Net cumulative DHA loss from the brain (DHA loss + DHA consumption) following SAH may be massive in some cases and is likely to impose a severe burden on the brain.
\nA current Western diet may provide sufficient amounts of FAs to compensate for the loss of other FAs, but not DHA. Current Western diets are characterized by very low intakes of long-chain omega-3 FAs and high intakes of other FAs, especially omega-6 FAs such as ARA and linoleic acid [48]. Thus, a significant imbalance between brain DHA loss and inadequate nutritional intake of omega-3 FAs may persist over the long term in SAH patients, hindering the recovery of DHA accretion in the brain required for normal neuronal function [35, 36].
\nLoss of EPA after SAH has not yet been examined; however, it is reasonable to assume that depletion of EPA from cerebral endothelial membranes may play a significant role in microvascular dysfunction after SAH. Indeed, EPA seems to have a more potent effect than DHA in the treatment of mood disorders, though the underlying mechanisms remain elusive [22].
\nWe coined the term “selective brain malnutrition” to describe the pathological consequences of EPA and DHA loss following SAH on the structure and function of the brain. This novel hypothesis of selective brain malnutrition offers a plausible explanation for some of the intriguing clinical features of SAH, including diffuse cerebral atrophy and the frequently observed long-lasting functional sequelae, such as cognitive dysfunction and mood disorders, that occur even in the absence of focal injury [5, 49]. Importantly, a higher omega-3 index has been associated with larger total brain and hippocampal volumes in observational studies in humans [50].
\nConsensus has emerged on the pressing need to find a multipronged therapeutic intervention to address the various deleterious effects of early brain injury (EBI) after SAH [51]. Nonetheless, the loss of brain DHA after SAH is likely to be an unrecognized effect of EBI, and in turn loss of DHA may represent a critical event in the pathogenesis of secondary brain injury after SAH. Depending on the severity of SAH, the cumulative burden of brain DHA loss may be massive and decreases endogenous neuroprotective capacity in the short term [12, 36]. Thus, unresolved homeostatic disturbances within the cerebral microenvironment may lead to neurovascular uncoupling, which may spread over the cerebral cortex in the most severe cases [52]. The loss of an entire series of signaling events required for maintenance of neurovascular network integrity may further increase the risk of focal injury, diffuse cerebral atrophy, and functional sequelae [37]. In this context, it is reasonable to assume that large-artery vasospasm may paradoxically be a compensatory mechanism to preserve tissue oxygen availability in the presence of progressive microvascular failure, i.e., when capillary transit time heterogeneity substantially increases [3, 31]. Unresolved inflammation may also induce hyperproliferation of arachnoid cap cells, which increases the risk of hydrocephalus [4]. Uncontrolled systemic complications, such as severe cardiopulmonary dysfunction, may further aggravate homeostatic disturbances and have devastating consequences on brain function [53].
\nTheoretically, EPA, DHA, and their respective SPMs possess the bioactive capacity to counteract the major homeostatic disturbances that occur after SAH. EPA-RvEs could reduce thromboinflammation at the cerebral microvasculature by inhibiting vasoconstriction, leukocyte transendothelial migration, and platelet aggregation [15, 26]. DHA and its derivatives may trigger the critical signals required to maintain functional neurovascular coupling and cell survival [16, 36, 37]. DHA-induced upregulation of the enzyme heme oxygenase 1 (HO-1) may accelerate the clearance of subarachnoid clots and thus decrease heme-induced cerebral inflammation [54]. SMPs may attenuate inflammation-induced hyperproliferation of arachnoid cap cells, further contributing to diminish the risk of hydrocephalus. SPMs may also provide multi-organ protection and enhance the immune response against infections.
\nFurthermore, the promising role of DHA derivatives in reducing microglial polarization toward an inflammatory phenotype may offer a novel approach to reduce the brain inflammation induced by neurosurgical trauma in surgically treated SAH patients [55]. Neurogenesis has also been identified in SAH patients, and thus DHA could represent a novel therapeutic strategy to improve neurological recovery by stimulating neurogenesis [56]. Moreover, subtle changes on microvascular function and synaptogenesis induced by EPA and DHA may improve cognitive function and mood and thus increase the likelihood of complete functional recovery of SAH patients.
\nThe theoretical framework described above provides scientific rationale for future clinical trials of omega-3 FAs in SAH patients. The disappointing results of RCTs of isolated pharmaceutical interventions in SAH could be overcome if a translational approach is correctly implemented [8]. In support of this notion, the recently published phase 3 REDUCE-IT trial provided a robust demonstration of the clinical efficacy and therapeutic potential of EPA to reduce cardiovascular events in chronic cardiovascular (CV) patients with hypertriglyceridemia [57]. Obviously, there are major differences between patients with chronic CV disease and hypertriglyceridemia and patients with SAH. Nevertheless, the considerable clinical benefits of EPA observed in patients with CV disease (who were already on statin therapy) may be due not only to the triglyceride-lowering effect of EPA. Interestingly, the results of the REDUCE-IT trial resemble those of the GISSI-Prevenzione trial conducted 20 years ago, in which a low-dose oral treatment of EPA plus DHA significantly reduced CV morbimortality in patients who had suffered a recent myocardial infarction and were already on aspirin treatment [58].
\nMinor changes in overall membrane FAs composition and the increase in local production of longer-acting SPM R-epimers after combined treatment with omega-3 FAs and aspirin or statins are likely to mediate a wide variety of biological effects and have a profound impact on cellular and multi-organ function [15]. Indeed, emerging evidence clearly indicates a strong association between a higher omega-3 index and major health benefits (reduced risk of both CV and all-cause mortality) over the long term [21]. However, the acute and critical nature of SAH imposes a particularly demanding therapeutic challenge as the homeostatic disturbances in the brain and other vital organs must be effectively addressed in the short term. An intervention based exclusively on oral supplementation with omega-3 FAs is unlikely to be fully effective on its own in the clinical context of SAH. However, the superiority of parenteral administration over oral or enteral administration of omega-3 FAs has been reliably demonstrated in short-term interventions [17, 59]. Parenteral administration of omega-3 FAs allows rapid delivery of higher doses of EPA and DHA without bioavailability issues and does not depend on the patient’s clinical condition. Indeed, the incorporation profiles of EPA and DHA in the transport and functional pools after a single parenteral dose are equivalent to up to several weeks of oral supplementation. EPA and DHA appear in PBMCs as rapidly as 6 hours after a single parenteral dose, thus highlighting the ability of parenterally administered omega-3 FAs to easily reach the innate immune system [59]. The concentration of omega-3 FAs in the main plasmatic fraction that supplies the brain and other vital organs (the NEFA pool) also increases rapidly after a single parenteral dose [17, 60]. Thus, the SPM precursors EPA and DHA seem to be rapidly and widely available to activate resolution of inflammation on demand in different organs after parenteral administration. Therefore, parenteral administration may be the most efficient way to deliver omega-3 FAs during the acute stage of SAH. This novel therapy is in accordance with the concept of pharmaconutrition, in which key nutrients are utilized as pharmacological agents and delivered in appropriate doses via the most efficient administration route [61]. Oral or enteral administration may be suitable for medium- or long-term treatment when the patient’s gastrointestinal function has completely recovered.
\nA regular supplementation dose for healthy subjects defined by several health associations worldwide is around 500–750 mg/day of EPA plus DHA and can be achieved by consuming a regular diet that contains two portions of fatty fish per week [62]. Therapeutic anti-inflammatory doses of EPA plus DHA are usually considered to be above 2 g/day [25]. A daily dose of at least 1 g EPA plus DHA/day (EPA > 60% DHA) has been shown to be effective in patients with depressive disorders [22]. EPA doses above 1.8 g/day seem to be required to produce clinically meaningful effects on endothelial and vascular function [63]. In patients with age-related cognitive decline, 900 mg DHA/day improved learning and memory function [64]. Importantly, omega-3 FAs doses can be significantly reduced by decreasing the dietary intake of omega-6 FAs. This fact likely explains the notably different dosages of EPA required to obtain beneficial outcomes in patients with chronic CV disease in a Japanese trial (1.8 g/day) and the REDUCE-IT trial (4 g/day) conducted in 11 Western countries [48, 57, 63].
\nThe therapeutic dose of parenteral fish oil (FO) to complement total parenteral nutrition (TPN) is of 0.1–0.2 g of FO/kg/day [59]. This dosage is equivalent to 1–2 ml/ kg/day of a specific FOLE that contains 10 g of FO/100 ml.
\nBioavailability refers to both the speed of absorption and the quantity of the substance absorbed in the gastrointestinal tract. The bioavailability of omega-3 FAs oral formulations should be carefully considered as it may have direct clinical implications [65]. The bioavailability of EPA and DHA depends on the chemical form in which they are bound (phospholipids > triglycerides > free fatty acids > ethyl esters) as well as their Galenic form (i.e., microencapsulation, emulsification) and also matrix effects (capsule ingestion with concomitant content of food, fat content in food). Galenic form and matrix effects are the most important factors that influence the bioavailability of EPA and DHA. Thus, administration of high-quality pharmaceutical formulations with fatty meals is necessary to ensure the effectiveness of oral therapy.
\nTo date, only two preclinical studies of omega-3 FAs in experimental models of SAH have been published. Yin et al. suggested that pre-treatment with omega-3 FAs by oral gavage elicited anti-inflammatory and anti-apoptotic effects in a rat model of SAH [66]. Zhang et al. showed intravenous administration of DHA may prevent oxidative stress-induced apoptosis by improving mitochondrial dynamics in a rat model of SAH induced by endovascular perforation [67]. However, the scarcity of preclinical studies on omega-3 FAs in SAH contrasts with the large number of experimental studies on ischemic stroke. The effects of omega-3 FAs (or specific derivatives) in neural tissue have been widely examined in experimental ischemia-reperfusion models [55, 68, 69]. These studies have consistently shown that omega-3 FAs significantly reduce cerebral infarction volume by around 40–50% and are associated with a drastic decrease in the neuroinflammatory response [70, 71]. Interestingly, the long-term neurobehavioral recovery in experimental models of ischemic stroke is associated with neuroprotective effects of DHA on both gray and white matter [55]. It is noteworthy that one of these studies used a specific FOLE that is widely approved for clinical use [70].
\nA limited number of omega-3 FAs interventional studies have been performed in SAH patients [13, 72, 73, 74]. The main characteristics and findings of these studies are summarized in Table 1. Two studies utilized EPA and DHA, and only one study included a parenteral regimen. In total, 229 patients with SAH have received an omega-3 FAs intervention; most patients were surgically treated (
Reference | \nType of study | \nPopulation, | \nIntervention | \nMain result | \n
---|---|---|---|---|
Yoneda et al. [73] | \nProspective, non-randomized | \n\n EPA = 73 | \nOral EPA: 1800 mg/day × 10 postoperative (PO) days | \nReduction in vasospasm and cerebral infarction | \n
Yoneda et al. [74] | \nRCT | \n\n EPA = 81 | \nOral EPA: 2700 mg/day × 30 PO days | \nReduction in vasospasm and cerebral infarction | \n
Nakagawa et al. [72] | \nRetrospective study | \n\n EPA + DHA = 55 | \nOral EPA: 1860 mg/day + oral DHA: 750 mg/day × 90 PO days | \nReduction in vasospasm and cerebral infarction | \n
Saito et al. [13] | \nPilot RCT | \n\n EPA + DHA = 20 | \nParenteral perioperative: 5 days Oral EPA: 1840 mg/day + oral DHA: 1520 mg/day × 8 weeks | \nNo postoperative intracranial bleeding complications Easy-to-implement intervention | \n
Summary of the features and outcomes of clinical interventional studies in SAH patients.
Evidence obtained over more than two decades in other clinical fields indicates omega-3 FAs interventions are unlikely to lead to serious clinical harm in SAH patients [25, 59]. Nevertheless, parenteral administration of omega-3 FAs may raise some safety concerns. Total parenteral nutrition is associated with an increased risk of complications in critically ill patients [9]. Furthermore, administration of lipid emulsions (LEs) may cause fat overload syndrome; the amount of fat administered and LE infusion rate are the primary risk factors. In this regard, it should be emphasized that the therapeutic dose of FO (0.1–0.2 g of FO/kg/day) is about one order of magnitude lower than that of regular LE (0.7–1.5 g of fat/kg/day) [59]. Additionally, the plasma clearance rate is faster for FAs administered in FOLE than soybean oil-based LEs. These unique features contribute to the good safety profile of FOLE. Fish oil has been widely used as a component of total parenteral nutrition and is associated with reduced rates of infection, shorter hospital stay, and decreased mortality, particularly in surgically treated patients [59].
\nFurthermore, isolated parenteral administration of FO has increasingly been used in pediatric patients with parenteral nutrition-associated liver disease (PNALD). Several case series published since 2006 have reported parenteral FO monotherapy (PFOM) remarkably improved clinical outcome of patients with PNALD [75]. Importantly, PFOM has demonstrated a good safety profile in these critically ill patients, even at FO doses up to 1.5 g FO/kg/day and overextended treatments beyond 4 weeks, well beyond the manufacturer’s recommendations.
\nThe aim of replacement FO therapy in PNALD is obviously different to SAH patients. Parenteral administration of FO is intended to address key nutrient deficiencies during the acute stage after SAH, and thus only short-term administration of a regular FO dose should be necessary. In fact, a 5-day parenteral perioperative regimen did not increase the occurrence of major postoperative complications in 19 surgically treated SAH patients [13]. Thus, there is good quality evidence to warrant further clinical trials of parenteral pharmaconutrition as an integral component of interventions with omega-3 FAs in SAH patients.
\nThe role of inflammation in the growth and rupture of intracranial aneurysms (IAs) has been increasingly recognized over the last few decades; however, the specific role of resolution of inflammation in IAs has not yet been considered [76]. Although the pathophysiology of atherosclerosis and the growth and rupture of IAs are distinct, both conditions are mediated by an underlying inflammatory process [77]. The progression of atherosclerotic plaques determines plaque morphology and the risk of rupture. The degree of macrophage infiltration plays a crucial role in the progression of atherosclerotic plaques. Interestingly, IAs have also been recently regarded as a macrophage-mediated inflammatory disease in which prostaglandin E2 and the master transcription factor NF-kB may be crucial drivers of inflammatory signals [78, 79]. It should be remembered that prostaglandin E2 is derived from the long-chain omega-6 FAs ARA and that EPA can inhibit the generation of eicosanoids from ARA and also downregulates the activity of NF-kB [25].
\nAtherosclerotic plaques readily incorporate omega-3 FAs, and a higher plaque EPA content is associated with a reduced number of foam cells and macrophages, as well as increased plaque stability, as determined by a well-formed fibrous cap [80]. Additionally, signs of defective resolution of inflammation have been identified in atherosclerotic plaques [81]. One major function of SPMs (particularly maresins) is to induce phenotypic conversion of macrophages, which decrease inflammation and promote tissue regeneration [16]. In animal models of atherosclerosis, a traditional Western high-fat diet disrupts the homeostasis of inflammation resolution by nutrigenetic modulation of the 12/15-LOX pathways, thereby inhibiting the generation of protective SPMs [81, 82]. These recent findings in atherosclerosis, particularly the involvement of docosanoids in vascular inflammation, provide biological plausibility that defective resolution of inflammation is implicated in the pathogenesis of IA growth and rupture.
\nHuman beings evolved, and their genetic patterns were established on a diet with an omega-6/omega-3 FAs ratio of 1/1, whereas in current Western diets, this ratio is around 16/1 [83]. Thus, this extreme nutritional imbalance in current Western diets should be seriously considered as a potential aggravating factor for the growth and rupture of IAs [48, 82]. This suggestion may appear somewhat counterintuitive considering the high prevalence of IAs with increased risk of rupture in the Japanese population, which has one of the highest dietary intakes of omega-3 FAs worldwide [48, 84]. However, nutritional deficiency of long-chain omega-3 FAs may not be the only factor associated with defective resolution of inflammation. Inter-individual and ethnic variations in the susceptibility to IA growth and rupture could be related to tissue-specific enzymatic deficiencies in the biosynthetic routes that regulate the resolution of inflammation. However, while defective resolution has already been associated with other chronic inflammatory diseases, it is not yet known whether enzymatic deficiencies contribute to IA growth and rupture, and this novel hypothesis requires further investigation [85, 86].
\nThe vital roles of EPA and DHA in the human body emphasize the evolutionary importance of maintaining efficient functional couplings between chemical and biological systems as well as between the vasculature and the brain [87]. Resolution of inflammation and endogenous neuroprotective signaling are interrelated processes that largely depend on EPA and DHA derivatives. This novel concept may open new avenues for public health interventions and innovative research in IAs and SAH.
\nAlthough nutrition has been traditionally viewed as a supportive measure, increasing evidence strongly suggests that a more balanced dietary intake of omega-6 and omega-3 FAs may represent the most efficient means of improving the status of inflammation resolution at the population level [48, 82, 83]. This specific dietary recommendation could contribute to decrease the risk of IAs growth and rupture and the devastating consequences of SAH, along with other important health benefits.
\nThe pathological significance of the loss of brain DHA after SAH has been widely ignored, even though strong preclinical evidence supports the hypothesis that the integrity of the neurovascular unit largely depends on high DHA enrichment. This previously unrecognized pathophysiological process may significantly increase the risk of secondary brain injury following SAH.
\nThe robust demonstration of the clinical efficacy of EPA in patients with chronic CV disease supports the encouraging results obtained in preliminary clinical studies of omega-3 FAs in SAH and warrants a large-scale RCT. It needs to be emphasized that DHA should always be included in neuroprotective interventions, as DHA plays an essential role in neural tissue and is the cornerstone for docosanoid generation. Parenteral pharmaconutrition with FO offers major clinical advantages for the treatment of SAH patients and should also be an integral component of omega-3 FAs interventions during the acute stage of the disease.
\nThe design of future RCTs of omega-3 FAs in SAH should bear in mind a potentially important factor. Clinical approaches that mainly focus on large-artery vasospasm may actually counteract the beneficial effects of omega-3 FAs and other neuroprotective interventions. The main rationale behind this seemingly paradoxical notion is based on both theoretical models and clinical perspectives [3, 31]. An unpublished subgroup analysis of our pilot pharmaconutrition trial of omega-3 FAs showed unexpected differences in the occurrence of cerebral infarction due to DCI between study centers, each of which had different clinical approaches to large-artery vasospasm [13]. In addition, a recently published observational study performed in the UK showed centers that screened for large-artery vasospasm using transcranial Doppler ultrasound (TCD) had poorer inhospital outcomes and similar rates of DCI diagnosis compared to centers that did not [88]. These results support the dissociation between large-artery vasospasm and clinical outcome that has been observed in major phase 3 RCTs in SAH [8]. Therefore, reliance on a surrogate clinical endpoint such as large-artery vasospasm may lead to the adoption of useless or even harmful clinical approaches [88, 89, 90, 91]. Indeed, some research centers in Europe do not include TCD ultrasound or endovascular rescue therapy in their treatment protocols for SAH patients [92].
\nMoreover, it would be clinically meaningful to determine if correlations exist between the omega-3 index and the concentrations of EPA and DHA as well as the status of inflammation resolution in the wall of ruptured and non-ruptured IAs. There may be a real opportunity for a readily implementable and low-cost therapy if the walls of IAs are as responsive to omega-3 FAs as atherosclerotic plaques.
\nThe interplay between omega-3 FAs and widely used drugs (aspirin and statins) that lead to the generation of longer-acting SPM R-epimers provides ample opportunities for future translational approaches in IAs and SAH. Indeed, combined therapies with omega-3 FAs and aspirin or statins could represent a viable, easy-to-implement therapeutic strategy for patients with unruptured IAs.
\nParenteral pharmaconutrition with FO could also be a clinically effective intervention for perioperative neuroprotection for patients subjected to other surgeries at high risk of neurological injury, such as carotid endarterectomy, cardiac surgery, or diverse neurosurgical procedures.
\nIn the future, new drug delivery systems capable of carrying synthetic analogues of SPMs could become a viable therapeutic strategy for patients with tissue-specific enzymatic deficiencies in the resolution pathways [93].
\nThe authors have no conflicts of interest to declare.
We express our appreciation to our patients from whom we have learned so much.
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