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• W2019929316 abstract "Induced pluripotent stem (iPS) cells reprogrammed from somatic cells have the potential to differentiate, under appropriate conditions, to any cell type. Recent studies, including two papers in this issue (Bilousova et al., 2011; Tolar et al., 2011), have demonstrated that iPS cells can differentiate into keratinocytes. Thus, iPS cells may provide a novel approach to applying regenerative medicine to cutaneous diseases such as epidermolysis bullosa. Induced pluripotent stem (iPS) cells reprogrammed from somatic cells have the potential to differentiate, under appropriate conditions, to any cell type. Recent studies, including two papers in this issue (Bilousova et al., 2011; Tolar et al., 2011), have demonstrated that iPS cells can differentiate into keratinocytes. Thus, iPS cells may provide a novel approach to applying regenerative medicine to cutaneous diseases such as epidermolysis bullosa. At the 2010 Annual Meeting of the Society for Investigative Dermatology in Atlanta, Georgia, among the hot topics were several abstracts reporting that induced pluripotent stem (iPS) cells can be differentiated into keratinocytes, suggesting that such cells can be applied to regenerative medicine in dermatology. Now, several months later, the full papers on these presentations are appearing in the literature. In this issue, two articles (Bilousova et al., 2011Bilousova G. Chen J. Roop D.R. Differentiation of mouse induced pluripotent stem cells into a multipotent keratinocyte lineage.J Invest Dermatol. 2011; 131: 857-864Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar; Tolar et al., 2011Tolar J. Xia L. Riddle M.J. et al.Induced pluripotent stem cells from individuals with recessive dystrophic epidermolysis bullosa.J Invest Dermatol. 2011; 131: 848-856Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar) report on differentiation of mouse and human iPS cells into keratinocytes. A complementary study (Itoh and Christiano, 2010Itoh M. Christiano A. Differentiation of human induced pluripotent stem (iPS) cells into keratinocytes.J Invest Dermatol. 2010; 130 (abstract): s83Google Scholar) is being prepared for publication (Itoh et al., personal communication). The translational focus of these papers centers on epidermolysis bullosa (EB), a group of heritable blistering diseases in which, as a result of mutations in as many as 14 different genes expressed in the epidermis and the cutaneous basement membrane zone, the skin and mucous membranes are extremely fragile, leading to blistering and erosions with considerable morbidity and mortality. No effective or specific treatment is currently available for EB, but significant progress has been made recently toward the development of DNA-, protein-, and cell-based therapies (Uitto et al., 2010Uitto J. McGrath J.A. Rodeck U. et al.Progress in epidermolysis bullosa research: toward treatment and cure.J Invest Dermatol. 2010; 130: 1778-1784Crossref PubMed Scopus (64) Google Scholar). Generation of functional skin from iPS cells may now provide an innovative approach to enhancing the regeneration and repair of damaged tissues in these patients. The development and use of iPS cells comprise a rapidly evolving field that emerged in 2006 with the demonstration that somatic cells, such as skin fibroblasts (Takahashi and Yamanaka, 2006Takahashi K. Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (16979) Google Scholar), epidermal keratinocytes (Aasen et al., 2008Aasen T. Raya A. Barrero M.J. et al.Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes.Nat Biotechnol. 2008; 11: 1276-1284Crossref Scopus (1067) Google Scholar), and hair follicle outer root sheath cells (Aasen and Belmonte, 2010Aasen T. Belmonte J.C. Isolation and cultivation of human keratinocytes from skin or plucked hair for the generation of induced pluripotent stem cells.Nat Protoc. 2010; 5: 371-382Crossref PubMed Scopus (213) Google Scholar) from adults can be reprogrammed to an embryonic stem (ES) cell-like state by addition of a few selected transcription factors (c-MYC, SOX2, OCT4, and KLF4) (Figure 1). Culturing and characterization of such cells then allow isolation of pluripotent cells with features of ES cells and the potential to differentiate into any cell type in the body. Several characteristics indicate the successful generation of iPS cells (Table 1), including a morphology similar to that of human ES cells (i.e., small size, prominent nuclei with a large nucleus-to-cytoplasm ratio, and tight and flat colonies with clear-cut, round edges) and a normal karyotype. Expression of several stem cell markers must be demonstrated by immunostaining or by reverse transcription–PCR—particularly expression of the NANOG gene, which is not used for induction of iPS cells. These reprogramming factors are thought to activate a network of transcriptional factors that in turn induce epigenetic changes, including demethylation of OCT4 and NANOG promoter sequences. The pluripotent capacity of these cells is then demonstrated by teratoma formation in vivo upon injection of iPS cells into immunocompromised mice, and confirming the contribution of iPS cells to cell lineages of endodermal, mesodermal, and ectodermal origin using germ layer–specific markers.Table 1Criteria for successful generation of induced pluripotent stem cellsCharacteristic morphology and normal karyotypeImmunostaining and increased gene expression of stem cell markers (OCT4, SOX2, NANOG)Silencing of the viral transgenesDemethylation of stem cell gene promoters (NANOG)Teratoma formation in vivo and contribution to all three germ layers Open table in a new tab Once newly generated iPS cells have been characterized and their pluripotent capacity has been verified, they can theoretically be differentiated into any one of several lineages in vitro using culture conditions that are directed toward each lineage. This general scheme has been shown to be successful in generating specialized, well-differentiated cells, such as cardiomyocytes, neural cells, osteoblasts, blood progenitor cells, and insulin-producing cells. The three papers cited above are the first to demonstrate differentiation of iPS cells to keratinocytes, albeit using different, complementary methods and approaches.Induced pluripotent cells can differentiate into keratinocytes for the regeneration of skin. Induced pluripotent cells can differentiate into keratinocytes for the regeneration of skin. The study by Bilousova et al., 2011Bilousova G. Chen J. Roop D.R. Differentiation of mouse induced pluripotent stem cells into a multipotent keratinocyte lineage.J Invest Dermatol. 2011; 131: 857-864Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar) demonstrates directed differentiation of mouse iPS cells in culture into a multipotent keratinocyte lineage capable of forming a fully differentiated epidermis, hair follicles, and sebaceous glands in a reconstitutive in vivo environment. The key in differentiating iPS cells toward the ectodermal lineage is the sequential application of retinoic acid (RA) and bone morphogenic protein 4 (BMP4), which resulted in keratin 14–positive epidermal stem cells. This stem cell population could be enriched by selective attachment to type IV collagen-coated surfaces, onto which the fully differentiated progeny does not attach. The study by Itoh et al. (personal communication) also reports successful generation of iPS cells, not only from normal human fibroblasts but also from fibroblasts isolated from the skin of patients with recessive dystrophic EB (RDEB). These investigators employed similar culture conditions using RA and BMP4, which allowed expedient differentiation of these iPS cells into keratinocytes. Importantly, these cells were used to generate three-dimensional skin equivalents, suggesting that they were fully functional. It is noteworthy that both of these studies drew on a foundation of knowledge in ES cell biology that has emerged in recent years. For example, both studies borrowed a page from earlier work attesting to the utility of RA and BMP4 in differentiating ES cells into keratinocytes and subsequent reprogramming of keratinocytes into a neural fate (Aberdam, 2004Aberdam D. Derivation of keratinocyte progenitor cells and skin formation from embryonic stem cells.Int J Dev Biol. 2004; 48: 203-206Crossref PubMed Scopus (62) Google Scholar; Grinnell and Bickenbach, 2007Grinnell K.L. Bickenbach J.R. Skin keratinocytes pre-treated with embryonic stem cell-conditioned medium or BMP4 can be directed to an alternative cell lineage.Cell Prolif. 2007; 40: 685-705Crossref PubMed Scopus (25) Google Scholar). In addition, the succession of markers that are activated as ES cells differentiate into keratinocytes provides a road map for monitoring the efficacy of directed differentiation of iPS cells into keratinocytes (Green et al., 2003Green H. Easley K. Iuchi S. Marker succession during the development of keratinocytes from cultured human embryonic stem cells.Proc Natl Acad Sci USA. 2003; 100: 15625-15630Crossref PubMed Scopus (149) Google Scholar). The study by Tolar et al., 2011Tolar J. Xia L. Riddle M.J. et al.Induced pluripotent stem cells from individuals with recessive dystrophic epidermolysis bullosa.J Invest Dermatol. 2011; 131: 848-856Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar takes a different approach. Instead of directed differentiation into keratinocytes in culture followed by skin-reconstitution assessment, these investigators used direct injection and teratoma formation to allow spontaneous differentiation of iPS cells into skin-like structures expressing keratinocyte markers. As a starting point, they used human fibroblasts or keratinocytes from normal individuals as well as from patients with RDEB, and they performed gene correction of the latter cells with a vector expressing type VII collagen. The differentiation of RDEB cells into corresponding iPS cells was similar to that observed for wild-type iPS cells, including the ability to differentiate spontaneously into structures resembling skin. Interestingly, these investigators also observed differentiation of these cells into hematopoietic lineages, which suggests that such cells could be used to generate autologous hematopoietic cells for grafting. Collectively, these studies suggest that iPS cells can be differentiated into keratinocytes and skin-like structures, with the potential of treating EB. An intriguing possibility related to the use of iPS cells for regenerative medicine in dermatology centers on the potential of combining iPS cell technology with revertant mosaicism, which clinically manifests as patches of normal skin in patients with heritable skin diseases such as EB (Almaani et al., 2010Almaani N. Nagy N. Liu L. et al.Revertant mosaicism in recessive dystrophic epidermolysis bullosa.J Invest Dermatol. 2010; 130: 1937-1940Crossref PubMed Scopus (46) Google Scholar; Pasmooij et al., 2010Pasmooij A.M. Garcia M. Escamez M.J. et al.Revertant mosaicism due to a second-site mutation in COL7A1 in a patient with recessive dystrophic epidermolysis bullosa.J Invest Dermatol. 2010; 130: 2407-2411Crossref PubMed Scopus (42) Google Scholar). These areas of skin reflect the presence of a second mutation in the clonal population of cells—as a result of back mutations, intragenic crossovers, or gene conversion—that negates the deleterious effects of the primary mutation and reverses the phenotype; this phenomenon has been dubbed “natural gene therapy” (Lai-Cheong et al., 2011Lai-Cheong J.E. McGrath J.A. Uitto J. Revertant mosaicism in skin: natural gene therapy.Trends Mol Med. 2011Abstract Full Text Full Text PDF Scopus (86) Google Scholar). Thus, generation of iPS cells from spontaneously revertant skin would provide an essentially unlimited number of patient-specific cells for grafting in diseases such as RDEB. Collectively, these studies attest to the potential of iPS cells for patient-specific stem cell therapy for skin diseases. The advantages of utilizing iPS cells for regenerative medicine over the ES cells are several. For example, the use of iPS cells obviates the ethical/political issues that have surrounded ES cells, especially in the United States. iPS cells can be autologous and patient specific, eliminating the issues relating to immune-based rejection of the grafts. Also, the generation of iPS cells can theoretically be scaled up, essentially providing an unlimited source of cells for medical application. So, when will iPS cell therapy be available for patients? Stem cell researchers agree that utility of iPS cells for medical applications will be a reality eventually but that their use is only in the early days of development (Vogel, 2010Vogel G. Stem cells: diseases in a dish take off.Science. 2010; 330: 1172-1173Crossref PubMed Scopus (12) Google Scholar). Among the several areas of uncertainty is the possibility that the transgenes encoding reprogramming factors, which are ordinarily inserted into target cells via retroviral vectors, may cause carcinogenesis and that inactivation of the viral genes will be incomplete, possibly leading to tumor formation. Okita et al., 2008Okita K. Nakagawa M. Hyenjong H. et al.Generation of mouse induced pluripotent stem cells without viral vectors.Science. 2008; 322: 949-953Crossref PubMed Scopus (1533) Google Scholar, seeking to circumvent the use of viral genes for transfection, found that introduction of the corresponding transcription factors in the form of proteins delivered to the cells allows induction of iPS cells without viral vectors. Even more intriguing is the recent demonstration that a simple, nonintegrating strategy of administering synthetic mRNAs for the transcription factors can result in rapid and efficient reprogramming of cells to pluripotency (Warren et al., 2010Warren L. Manos P.D. Ahfeldt T. et al.Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA.Cell Stem Cell. 2010; 7: 618-630Abstract Full Text Full Text PDF PubMed Scopus (1834) Google Scholar). Because the exogenously administered RNA molecules are rapidly degraded, the DNA backbone of the reprogrammed cells remains intact and is indistinguishable from that of the original wild-type cells. Finally, the use of iPS cells to treat heritable skin diseases will require transduction of the missing or nonfunctional gene to the cells (such as type VII collagen into iPS cells generated from patients with RDEB) for patients who do not display revertant mosaicism. Here again, the question of carcinogenesis, even if a hypothetical possibility, has been raised when retroviral vectors have been used to insert the transgene. Along these lines, gene-correction strategies, such as zinc-finger nuclease technology, have emerged as viable alternatives for the repair of mutations in iPS cells (Urnov et al., 2010Urnov F.D. Rebar E.J. Holmes M.C. et al.Genome editing with engineered zinc finger nucleases.Nat Rev Genet. 2010; 11: 636-646Crossref PubMed Scopus (1363) Google Scholar). It is clear at this point that iPS cells can provide a useful model for studying the mechanisms of diseases, and these cell systems can be used for large-scale screens in the development of candidate drugs. Novel technologies relating to iPS cells are rapidly being developed (Csete, 2010Csete M. Translational prospects for human induced pluripotent stem cells.Regen Med. 2010; 5: 09-19Crossref Scopus (38) Google Scholar; Warren et al., 2010Warren L. Manos P.D. Ahfeldt T. et al.Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA.Cell Stem Cell. 2010; 7: 618-630Abstract Full Text Full Text PDF PubMed Scopus (1834) Google Scholar), and the three papers highlighted above mark a significant milestone in skin biology because they demonstrate differentiation of both human and mouse iPS cells into keratinocytes. Refinements in the generation of such cells may provide treatment options for heritable skin diseases such as RDEB sooner than we realize. I thank Dr. Angela Christiano for stimulating discussions, helpful suggestions, and the sharing of unpublished data. Carol Kelly assisted in manuscript preparation." @default.
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• W2019929316 date "2011-04-01" @default.
• W2019929316 modified "2023-09-27" @default.
• W2019929316 title "Regenerative Medicine for Skin Diseases: iPS Cells to the Rescue" @default.
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