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• W2510157877 abstract "Cellular reprogramming technology has created new opportunities in understanding human disease, drug discovery, and regenerative medicine. While a combinatorial code was initially found to reprogram somatic cells to pluripotency, a “second generation” of cellular reprogramming involves lineage-restricted transcription factors and microRNAs that directly reprogram one somatic cell to another. This technology was enabled by gene networks active during development, which induce global shifts in the epigenetic landscape driving cell fate decisions. A major utility of direct reprogramming is the potential of harnessing resident support cells within damaged organs to regenerate lost tissue by converting them into the desired cell type in situ. Here, we review the progress in direct cellular reprogramming, with a focus on the paradigm of in vivo reprogramming for regenerative medicine, while pointing to hurdles that must be overcome to translate this technology into future therapeutics. Cellular reprogramming technology has created new opportunities in understanding human disease, drug discovery, and regenerative medicine. While a combinatorial code was initially found to reprogram somatic cells to pluripotency, a “second generation” of cellular reprogramming involves lineage-restricted transcription factors and microRNAs that directly reprogram one somatic cell to another. This technology was enabled by gene networks active during development, which induce global shifts in the epigenetic landscape driving cell fate decisions. A major utility of direct reprogramming is the potential of harnessing resident support cells within damaged organs to regenerate lost tissue by converting them into the desired cell type in situ. Here, we review the progress in direct cellular reprogramming, with a focus on the paradigm of in vivo reprogramming for regenerative medicine, while pointing to hurdles that must be overcome to translate this technology into future therapeutics. The concept that differentiated cells are plastic and can be reprogrammed to alternate cell fates was first suggested by the cloning experiments of Gurdon (Gurdon et al., 1958Gurdon J.B. Elsdale T.R. Fischberg M. Sexually mature individuals of Xenopus laevis from the transplantation of single somatic nuclei.Nature. 1958; 182: 64-65Crossref PubMed Scopus (286) Google Scholar) and later Wilmut (Campbell et al., 1996Campbell K.H. McWhir J. Ritchie W.A. Wilmut I. Sheep cloned by nuclear transfer from a cultured cell line.Nature. 1996; 380: 64-66Crossref PubMed Scopus (1255) Google Scholar). In these studies, undefined factors in the oocyte cytoplasm were found to induce somatic cells to assume an embryonic state. Embryonic and fetal development ensued, culminating in live births and surprisingly normal postnatal development. This observation was the original form of “in vivo” cellular reprogramming. Nearly 30 years later, a single myoblast cDNA encoding the transcription factor MyoD, expressed “where it is not normally,” was shown to convert fibroblasts directly to myoblasts (Davis et al., 1987Davis R.L. Weintraub H. Lassar A.B. Expression of a single transfected cDNA converts fibroblasts to myoblasts.Cell. 1987; 51: 987-1000Abstract Full Text PDF PubMed Scopus (2049) Google Scholar). The cells did not revert to a pluripotent state before assuming their new fate—and the paradigm for what is now termed “direct reprogramming” was born, at least in vitro. These findings violated the prevailing view of somatic cell fate as inviolate and immutable but were consistent with heterokaryon experiments that observed rapid nuclear reprogramming of fibroblasts upon fusion with myocytes (Blau et al., 1985Blau H.M. Pavlath G.K. Hardeman E.C. Chiu C.P. Silberstein L. Webster S.G. Miller S.C. Webster C. Plasticity of the differentiated state.Science. 1985; 230: 758-766Crossref PubMed Scopus (534) Google Scholar). However, the observation that a single factor could completely convert cells into distantly related cell fates turned out to be the exception rather than the rule. As critical lineage-enriched transcription factors like MyoD were discovered for various cell types during development, each failed to exhibit a MyoD-like ability to convert fibroblasts into a new fate, although C/EBPα was notable for its sufficiency to convert lymphoid cells into closely related myeloid cells of the hematopoietic system (Xie et al., 2004Xie H. Ye M. Feng R. Graf T. Stepwise reprogramming of B cells into macrophages.Cell. 2004; 117: 663-676Abstract Full Text Full Text PDF PubMed Scopus (619) Google Scholar). The notion that cell fate is, in fact, mutable and malleable finally took hold when Yamanaka showed that a cocktail of a few cell fate-changing transcription factors profoundly redirected somatic cells to a state of pluripotency (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 (12860) Google Scholar). This combinatorial approach paved the way to feverish activity in nuclear reprogramming. Much effort focused on refining methods to drive differentiated cells to a pluripotent state in various species and discovering the mechanisms. However, others began asking whether combinations of transcription factors could convert cell fates without first dedifferentiating the cells to pluripotency. In recent years, a combinatorial transcriptional “code” to directly reprogram cells toward specific lineages has emerged for many cell types. As a result, the Waddington model of cell differentiation as a determinant process has been revised to reflect an alternate view—that cell fate can readily be altered given appropriate conditions and cues (Figure 1) (Ladewig et al., 2013Ladewig J. Koch P. Brustle O. Leveling Waddington: The emergence of direct programming and the loss of cell fate hierarchies.Nat. Rev. Mol. Cell Biol. 2013; 14: 225-236Crossref Scopus (120) Google Scholar). In this Review, we briefly summarize the path to such discoveries in vitro but largely focus on more recent advances in harnessing direct reprogramming strategies for in vivo regeneration, which is likely the most powerful use of this technology. Specifically, this strategy involves re-purposing cells in damaged tissue in situ to regenerate organs from within, providing an alternative to exogenous cell-based therapeutic approaches. A common theme has emerged for multiple tissues—the native environment often contains local unknown cues that enhance the quality and efficiency of direct reprogramming. In 2006, Takahashi and Yamanaka showed that a cocktail of four specific transcription factors could, ex vivo, convert differentiated fibroblasts to a pluripotent state resembling embryonic stem cells derived from the blastocyst inner cell mass (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 (12860) Google Scholar). Their pioneering studies of induced pluripotent stem (iPS) cells established “reprogramming” as a transformative technology for biomedicine. iPS cell technology is a robust and ethically acceptable way to convert differentiated cells to a pluripotent state; the iPS cells can then be directed, by factors important for development and differentiation, to form functional differentiated cells of a variety of lineages. These studies established the paradigm that differentiation is not a dead end. Rather, genetic and epigenetic cues can reverse cell fate to a more primitive state through large-scale alterations in gene expression and chromatin status that have been carefully mapped during reprogramming of somatic cells to iPS cells (reviewed in Zaret and Mango, 2016Zaret K.S. Mango S.E. Pioneer transcription factors, chromatin dynamics, and cell fate control.Curr. Opin. Genet. Dev. 2016; 37: 76-81Crossref PubMed Google Scholar). Transient introduction of Yamanaka factors in conjunction with soluble lineage-specific signals has also been used to efficiently generate multiple cell types and has been reviewed elsewhere (Zhu et al., 2015Zhu S. Wang H. Ding S. Reprogramming fibroblasts toward cardiomyocytes, neural stem cells and hepatocytes by cell activation and signaling-directed lineage conversion.Nat. Protoc. 2015; 10: 959-973Crossref PubMed Google Scholar). Efforts to use a combinatorial approach for direct lineage conversion have been built on decades of developmental biology research. Numerous studies in flies, zebrafish, chicks, mice, and other model organisms have defined transcription factors that control cell fate during embryonic and fetal development and revealed gene networks that regulate cell fate. However, apart from MyoD and C/EBPα, single factors have not been sufficient for cellular reprogramming for most tissues. Nevertheless, the field was poised to leverage the combinatorial screening approach first used for iPS cell reprogramming by Takahashi and Yamanaka. Combinatorial screening entails identifying a pool of candidate genes encoding, for instance, transcription factors or microRNAs (miRNAs) that regulate cell fate or differentiation, testing the ability of the pool to convert fibroblasts to a differentiated cell fate of interest, and then using a “minus one” strategy to identify essential factors and pinpoint a minimal combination required for cell fate conversion. The first breakthroughs were reported for in vitro combinatorial reprogramming of fibroblasts to unrelated cell types, namely cardiomyocytes and neurons. The advances in this area that set the stage for in vivo reprogramming are briefly summarized below. After starting with nearly 20 transcription factors and a similar number of miRNAs, Ieda et al. reported that a combination of three cardiac developmental transcription factors—Gata4, Mef2c, and Tbx5 (GMT)—reprogrammed dermal or cardiac fibroblasts to induced cardiomyocyte-like cells (iCMs) (Figure 2A) (Ieda et al., 2010Ieda M. Fu J.D. Delgado-Olguin P. Vedantham V. Hayashi Y. Bruneau B.G. Srivastava D. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors.Cell. 2010; 142: 375-386Abstract Full Text Full Text PDF PubMed Scopus (1348) Google Scholar). Ectopic expression of these factors was required for ∼2 weeks, after which the reprogramming event was epigenetically stable. Interestingly, missense mutations in GATA4 and TBX5 cause similar congenital heart defects in humans. Moreover, the two factors they encode physically interact to regulate cardiac gene expression (Basson et al., 1997Basson C.T. Bachinsky D.R. Lin R.C. Levi T. Elkins J.A. Soults J. Grayzel D. Kroumpouzou E. Traill T.A. Leblanc-Straceski J. et al.Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome.Nat. Genet. 1997; 15: 30-35Crossref PubMed Scopus (774) Google Scholar, Garg et al., 2003Garg V. Kathiriya I.S. Barnes R. Schluterman M.K. King I.N. Butler C.A. Rothrock C.R. Eapen R.S. Hirayama-Yamada K. Joo K. et al.GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5.Nature. 2003; 424: 443-447Crossref PubMed Scopus (752) Google Scholar, Maitra et al., 2009Maitra M. Schluterman M.K. Nichols H.A. Richardson J.A. Lo C.W. Srivastava D. Garg V. Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development.Dev. Biol. 2009; 326: 368-377Crossref PubMed Scopus (98) Google Scholar), consistent with their combinatorial role in reprogramming. Lineage tracing approaches demonstrated that during reprogramming with GMT, fibroblasts did not pass through a mesodermal or cardiac progenitor stage, suggesting a more direct conversion from one postnatal cell type to another. Consistent with this observation, the iCMs that were more fully reprogrammed had electrophysiological properties most similar to those of adult ventricular cardiomyocytes. The generation of iCMs with GMT addressed a nearly 25-year quest to achieve a MyoD-like event for cardiac muscle. However, the in vitro efficiency was limited, and most of the iCMs were only partially reprogrammed, suggesting that other factors may enhance reprogramming, at least in vitro. As might be expected for a new technology, other combinations of factors in vitro were later found to convert fibroblasts to iCMs with greater efficiency (reviewed in Srivastava and Yu, 2015Srivastava D. Yu P. Recent advances in direct cardiac reprogramming.Curr. Opin. Genet. Dev. 2015; 34: 77-81Crossref PubMed Google Scholar). Additional transcription factors such as Hand2 (Song et al., 2012Song K. Nam Y.J. Luo X. Qi X. Tan W. Huang G.N. Acharya A. Smith C.L. Tallquist M.D. Neilson E.G. et al.Heart repair by reprogramming non-myocytes with cardiac transcription factors.Nature. 2012; 485: 599-604Crossref PubMed Scopus (563) Google Scholar, Srivastava et al., 1997Srivastava D. Thomas T. Lin Q. Kirby M.L. Brown D. Olson E.N. Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND.Nat. Genet. 1997; 16: 154-160Crossref PubMed Scopus (479) Google Scholar) and miRNAs such as the muscle-specific miRNAs miR-1 and miR-133 (Chen et al., 2006Chen J.F. Mandel E.M. Thomson J.M. Wu Q. Callis T.E. Hammond S.M. Conlon F.L. Wang D.Z. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation.Nat. Genet. 2006; 38: 228-233Crossref PubMed Scopus (1653) Google Scholar, Heidersbach et al., 2013Heidersbach A. Saxby C. Carver-Moore K. Huang Y. Ang Y.S. de Jong P.J. Ivey K.N. Srivastava D. microRNA-1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart.eLife. 2013; 2: e01323Crossref PubMed Scopus (0) Google Scholar, Muraoka et al., 2014Muraoka N. Yamakawa H. Miyamoto K. Sadahiro T. Umei T. Isomi M. Nakashima H. Akiyama M. Wada R. Inagawa K. et al.MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures.EMBO J. 2014; 33: 1565-1581Crossref PubMed Scopus (98) Google Scholar, Zhao et al., 2007Zhao Y. Ransom J.F. Li A. Vedantham V. von Drehle M. Muth A.N. Tsuchihashi T. McManus M.T. Schwartz R.J. Srivastava D. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2.Cell. 2007; 129: 303-317Abstract Full Text Full Text PDF PubMed Scopus (954) Google Scholar, Zhao et al., 2005Zhao Y. Samal E. Srivastava D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis.Nature. 2005; 436: 214-220Crossref PubMed Scopus (1138) Google Scholar) increased the conversion rate in vitro. A combination of four miRNAs—miR-1, miR-133, miR-208, and miR-499—converted mouse fibroblasts to cardiac myocytes in the absence of any exogenous transcription factors. The efficiency of the conversion was improved by JAK inhibitor I (Jayawardena et al., 2012Jayawardena T.M. Egemnazarov B. Finch E.A. Zhang L. Payne J.A. Pandya K. Zhang Z. Rosenberg P. Mirotsou M. Dzau V.J. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes.Circ. Res. 2012; 110: 1465-1473Crossref PubMed Scopus (358) Google Scholar). Similarly, inhibiting TGF-β signaling (Ifkovits et al., 2014Ifkovits J.L. Addis R.C. Epstein J.A. Gearhart J.D. Inhibition of TGFβ signaling increases direct conversion of fibroblasts to induced cardiomyocytes.PLoS ONE. 2014; 9: e89678Crossref PubMed Scopus (0) Google Scholar, Zhao et al., 2015Zhao Y. Londono P. Cao Y. Sharpe E.J. Proenza C. O’Rourke R. Jones K.L. Jeong M.Y. Walker L.A. Buttrick P.M. et al.High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling.Nat. Commun. 2015; 6: 8243Crossref PubMed Google Scholar) or the epigenetic regulator Bmi1 (Zhou et al., 2016Zhou Y. Wang L. Vaseghi H.R. Liu Z. Lu R. Alimohamadi S. Yin C. Fu J.D. Wang G.G. Liu J. Qian L. Bmi1 is a key epigenetic barrier to direct cardiac reprogramming.Cell Stem Cell. 2016; 18: 382-395Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar) appeared to break down barriers to reprogramming and increase conversion efficiency. Conversely, activating Fgf and Vegf signaling with GMT greatly increased yield of beating cardiomyocytes by activating Akt (Yamakawa et al., 2015Yamakawa H. Muraoka N. Miyamoto K. Sadahiro T. Isomi M. Haginiwa S. Kojima H. Umei T. Akiyama M. Kuishi Y. et al.Fibroblast growth factors and vascular endothelial growth factor promote cardiac reprogramming under defined conditions.Stem Cell Reports. 2015; 5: 1128-1142Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar), while overexpression of Akt1 also resulted in more efficient generation of beating cells, particularly in mouse embryonic fibroblasts (Zhou et al., 2015Zhou H. Dickson M.E. Kim M.S. Bassel-Duby R. Olson E.N. Akt1/protein kinase B enhances transcriptional reprogramming of fibroblasts to functional cardiomyocytes.Proc. Natl. Acad. Sci. USA. 2015; 112: 11864-11869Crossref PubMed Scopus (46) Google Scholar). In a different approach involving reprogramming of fibroblasts toward an early mesodermal progenitor, mouse embryonic fibroblasts were converted to differentiated cardiomyocytes by transient overexpression of the “Yamanaka factors” followed by expression of cardiogenic growth factors (Efe et al., 2011Efe J.A. Hilcove S. Kim J. Zhou H. Ouyang K. Wang G. Chen J. Ding S. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy.Nat. Cell Biol. 2011; 13: 215-222Crossref PubMed Scopus (421) Google Scholar). However, the maturity of the cells was similar to that of cardiomyocytes derived from pluripotent stem cells. Efforts to translate cardiac reprogramming technology from mice to humans proved difficult, as it became increasingly clear that human fibroblasts could not be converted by GMT or other combinations of factors capable of reprogramming mouse cells. Nonetheless, after screening for additional factors, several groups reported that overlapping cocktails of factors resulted in a degree of reprogramming comparable to that of mouse fibroblasts (Fu et al., 2013Fu J.D. Stone N.R. Liu L. Spencer C.I. Qian L. Hayashi Y. Delgado-Olguin P. Ding S. Bruneau B.G. Srivastava D. Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state.Stem Cell Reports. 2013; 1: 235-247Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, Nam et al., 2013Nam Y.J. Song K. Luo X. Daniel E. Lambeth K. West K. Hill J.A. DiMaio J.M. Baker L.A. Bassel-Duby R. Olson E.N. Reprogramming of human fibroblasts toward a cardiac fate.Proc. Natl. Acad. Sci. USA. 2013; 110: 5588-5593Crossref PubMed Scopus (231) Google Scholar, Wada et al., 2013Wada R. Muraoka N. Inagawa K. Yamakawa H. Miyamoto K. Sadahiro T. Umei T. Kaneda R. Suzuki T. Kamiya K. et al.Induction of human cardiomyocyte-like cells from fibroblasts by defined factors.Proc. Natl. Acad. Sci. USA. 2013; 110: 12667-12672Crossref PubMed Scopus (127) Google Scholar). A solely chemical approach using several small-molecule epigenetic regulators also efficiently converted human fibroblasts to beating cardiomyocytes—advancing the therapeutic potential of direct reprogramming strategies (Cao et al., 2016Cao N. Huang Y. Zheng J. Spencer C.I. Zhang Y. Fu J. Nie B. Wang H. Ma T. Xu T. et al.Conversion of human fibroblasts into functional cardiomyocytes by small molecules.Science. 2016; 352: 1216-1220Crossref PubMed Scopus (87) Google Scholar). In parallel with advances in direct cardiac reprogramming, a similar combinatorial approach was being used to convert mouse embryonic and fetal fibroblasts to functional neurons ex vivo. In one study, the combination of transcription factors Ascl1, Brn2 (also called Pou3f2), and Myt1l converted fibroblasts to cells that expressed neuron-specific proteins, generated action potentials, and formed functional synapses (Vierbuchen et al., 2010Vierbuchen T. Ostermeier A. Pang Z.P. Kokubu Y. Südhof T.C. Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors.Nature. 2010; 463: 1035-1041Crossref PubMed Scopus (1616) Google Scholar). In this combination, Ascl1 functioned as a “pioneer” factor to initiate chromatin changes and recruit the other two factors (Wapinski et al., 2013Wapinski O.L. Vierbuchen T. Qu K. Lee Q.Y. Chanda S. Fuentes D.R. Giresi P.G. Ng Y.H. Marro S. Neff N.F. et al.Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons.Cell. 2013; 155: 621-635Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar). Soon thereafter, non-neurogenic astroglia from mouse cerebral cortex were converted by neuronal reprogramming to specific sub-types of neurons capable of forming synapses in culture (Heinrich et al., 2010Heinrich C. Blum R. Gascón S. Masserdotti G. Tripathi P. Sánchez R. Tiedt S. Schroeder T. Götz M. Berninger B. Directing astroglia from the cerebral cortex into subtype specific functional neurons.PLoS Biol. 2010; 8: e1000373Crossref PubMed Scopus (209) Google Scholar). As with iCMs, the conversion to induced neurons (iNs) occurred in the absence of cell division and produced distinct neuronal subtypes, depending on which transcription factors were expressed. For example, expression of the dorsal telencephalic fate determinant neurogenin-2-directed cortical astroglia to generate synapse-forming glutamatergic neurons, whereas Dlx2, a ventral telencephalic fate determinant, induced a GABAergic identity. Under the appropriate culture conditions, a single factor, Sox2, converted fibroblasts to a neuronal fate, suggesting that optimizing culture conditions and signaling pathways within cells could simplify the reprogramming cocktail in certain settings, even with individual factors (Ring et al., 2012Ring K.L. Tong L.M. Balestra M.E. Javier R. Andrews-Zwilling Y. Li G. Walker D. Zhang W.R. Kreitzer A.C. Huang Y. Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor.Cell Stem Cell. 2012; 11: 100-109Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar). Ultimately, several groups succeeded in converting human fibroblasts directly to dopaminergic neurons (Caiazzo et al., 2011Caiazzo M. Dell’Anno M.T. Dvoretskova E. Lazarevic D. Taverna S. Leo D. Sotnikova T.D. Menegon A. Roncaglia P. Colciago G. et al.Direct generation of functional dopaminergic neurons from mouse and human fibroblasts.Nature. 2011; 476: 224-227Crossref PubMed Scopus (553) Google Scholar, Pfisterer et al., 2011Pfisterer U. Kirkeby A. Torper O. Wood J. Nelander J. Dufour A. Björklund A. Lindvall O. Jakobsson J. Parmar M. Direct conversion of human fibroblasts to dopaminergic neurons.Proc. Natl. Acad. Sci. USA. 2011; 108: 10343-10348Crossref PubMed Scopus (409) Google Scholar), spinal motor neurons (Son et al., 2011Son E.Y. Ichida J.K. Wainger B.J. Toma J.S. Rafuse V.F. Woolf C.J. Eggan K. Conversion of mouse and human fibroblasts into functional spinal motor neurons.Cell Stem Cell. 2011; 9: 205-218Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar), and oligodendroglia (Yang et al., 2013Yang N. Zuchero J.B. Ahlenius H. Marro S. Ng Y.H. Vierbuchen T. Hawkins J.S. Geissler R. Barres B.A. Wernig M. Generation of oligodendroglial cells by direct lineage conversion.Nat. Biotechnol. 2013; 31: 434-439Crossref PubMed Scopus (153) Google Scholar). The early direct conversion approaches induced a one-for-one exchange of cell types but did not provide a way to expand cell populations, as the converted cells rapidly exited the cell cycle. In 2012, several groups designed screens to generate expandable neural stem cells from fibroblasts by combinatorial direct conversion (Ring et al., 2012Ring K.L. Tong L.M. Balestra M.E. Javier R. Andrews-Zwilling Y. Li G. Walker D. Zhang W.R. Kreitzer A.C. Huang Y. Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor.Cell Stem Cell. 2012; 11: 100-109Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar, Thier et al., 2012Thier M. Wörsdörfer P. Lakes Y.B. Gorris R. Herms S. Opitz T. Seiferling D. Quandel T. Hoffmann P. Nöthen M.M. et al.Direct conversion of fibroblasts into stably expandable neural stem cells.Cell Stem Cell. 2012; 10: 473-479Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar). This approach avoided reversion to pluripotency, which may carry risks for generating oncogenic cells in vivo. At the same time, it generated an expandable intermediate cell population of neural stem cells that could be then differentiated to form specific neuronal subtypes. Similarly, expandable cardiac progenitors were generated by forcing human dermal fibroblasts to express mammalian ETS2 and MESP, both orthologs of genes essential for generating cardiac progenitors in the ascidian Ciona (Islas et al., 2012Islas J.F. Liu Y. Weng K.C. Robertson M.J. Zhang S. Prejusa A. Harger J. Tikhomirova D. Chopra M. Iyer D. et al.Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors.Proc. Natl. Acad. Sci. USA. 2012; 109: 13016-13021Crossref PubMed Scopus (96) Google Scholar). Earlier this year, two groups independently developed a chemical approach to convert mouse fibroblasts to an early cardiac progenitor state that could be maintained as transient amplifying progenitors. The progenitors retained multipotency and developed into cardiomyocytes, endothelial cells, and smooth muscle cells (Lalit et al., 2016Lalit P.A. Salick M.R. Nelson D.O. Squirrell J.M. Shafer C.M. Patel N.G. Saeed I. Schmuck E.G. Markandeya Y.S. Wong R. et al.Lineage reprogramming of fibroblasts into proliferative induced cardiac progenitor cells by defined factors.Cell Stem Cell. 2016; 18: 354-367Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, Zhang et al., 2016Zhang Y. Cao N. Huang Y. Spencer C.I. Fu J.D. Yu C. Liu K. Nie B. Xu T. Li K. et al.Expandable cardiovascular progenitor cells reprogrammed from fibroblasts.Cell Stem Cell. 2016; 18: 368-381Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). In another study, mouse fibroblasts were chemically converted to multipotent neural stem cells (Zhang et al., 2016Zhang M. Lin Y.H. Sun Y.J. Zhu S. Zheng J. Liu K. Cao N. Li K. Huang Y. Ding S. Pharmacological Reprogramming of Fibroblasts into Neural Stem Cells by Signaling-Directed Transcriptional Activation.Cell Stem Cell. 2016; 18: 653-667Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). In these studies, the chemical cocktails appear to induce fibroblast conversion into an epigenetically unstable state closer to pluripotency followed by redirection into cardiac or neuronal fates. Not surprisingly, resulting cells were most similar in maturity to ones derived from pluripotent stem cells. Overall, studies of direct conversion have identified many new combinations of factors that alter cell fate, including transcription factors described above, chemicals (Ladewig et al., 2012Ladewig J. Mertens J. Kesavan J. Doerr J. Poppe D. Glaue F. Herms S. Wernet P. Kögler G. Müller F.J. et al.Small molecules enable highly efficient neuronal conversion of human fibroblasts.Nat. Methods. 2012; 9: 575-578Crossref PubMed Scopus (151) Google Scholar, Liu et al., 2016Liu K. Yu C. Xie M. Li K. Ding S. Chemical Modulation of Cell Fate in Stem Cell Therapeutics and Regenerative Medicine.Cell Chem. Biol. 2016; 23: 893-916Abstract Full Text Full Text PDF PubMed Google Scholar), microRNAs (Yoo et al., 2011Yoo A.S. Sun A.X. Li L. Shcheglovitov A. Portmann T. Li Y. Lee-Messer C. Dolmetsch R.E. Tsien R.W. Crabtree G.R. MicroRNA-mediated conversion of human fibroblasts to neurons.Nature. 2011; 476: 228-231Crossref PubMed Scopus (524) Google Scholar), and combinations thereof (Wang et al., 2014Wang H. Cao N. Spencer C.I. Nie B. Ma T. Xu T. Zhang Y. Wang X. Srivastava D. Ding S. Small molecules enable cardiac reprogramming of mouse fibroblasts with a single factor, Oct4.Cell Rep. 2014; 6: 951-960Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar), as well as single transcription factors with appropriate culture conditions (Ring et al., 2012Ring K.L. Tong L.M. Balestra M.E. Javier R. Andrews-Zwilling Y. Li G. Walker D. Zhang W.R. Kreitzer A.C. Huang Y. Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor.Cell Stem Cell. 2012; 11: 100-109Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar). The various approaches share the common goal of making direct conversion more experimentally tractable, robust, and safe. Blood cells and other cell types have also been obtained in vitro by direct conversion (Batta et al., 2016Batta K. Menegatti S. Garcia-Alegria E. Florkowska M. Lacaud G. Kouskoff V. Recent Advances in the In Vitro Derivation of Blood Cell Populations.Stem Cells Transl Med. 2016; (2016-0039)Crossref PubMed Scopus (6) Google Scholar, Szabo et al., 2010Szabo E. Rampalli S. Risueño R.M. Schnerch A. Mitchell R. Fiebig-Comyn A. Levadoux-Martin M. Bhatia M. Direct conversion of human fibroblasts to multilineage blood progenitors.Nature. 2010; 468: 521-526Crossref PubMed Scopus (486) Google Scholar, Xie et al., 2004Xie H. Ye M. Feng R. Graf T. Stepwise reprogramming of B cells into macrophages.Cell. 2004; 117: 663-676Abstract Full Text Full Text PDF PubMed Scopus (619) Google Scholar). The studies discussed above point to the utility of in vitro direct reprogramming, particularly as it pertains to cell-based therapies and disease modeling. Thus, within less than a decade, in vitro reprogramming has become a rich and vigorous field, and covering it comprehensively is be" @default.
• W2510157877 created "2016-09-16" @default.
• W2510157877 creator A5000381401 @default.
• W2510157877 creator A5090670388 @default.
• W2510157877 date "2016-09-01" @default.
• W2510157877 modified "2023-10-18" @default.
• W2510157877 title "In Vivo Cellular Reprogramming: The Next Generation" @default.
• W2510157877 cites W1567266181 @default.
• W2510157877 cites W1580667945 @default.
• W2510157877 cites W1586830290 @default.
• W2510157877 cites W1758604915 @default.
• W2510157877 cites W1771186062 @default.
• W2510157877 cites W1874729010 @default.
• W2510157877 cites W1934209312 @default.
• W2510157877 cites W1966969776 @default.
• W2510157877 cites W1967729506 @default.
• W2510157877 cites W1968310639 @default.
• W2510157877 cites W1970894097 @default.
• W2510157877 cites W1972984824 @default.
• W2510157877 cites W1980130957 @default.
• W2510157877 cites W1986903527 @default.
• W2510157877 cites W1987167495 @default.
• W2510157877 cites W1987171954 @default.
• W2510157877 cites W1987618226 @default.
• W2510157877 cites W1989457690 @default.
• W2510157877 cites W1990670198 @default.
• W2510157877 cites W1991533533 @default.
• W2510157877 cites W1993326104 @default.
• W2510157877 cites W1998147947 @default.
• W2510157877 cites W2001419937 @default.
• W2510157877 cites W2003756136 @default.
• W2510157877 cites W2006919788 @default.
• W2510157877 cites W2008747758 @default.
• W2510157877 cites W2009876840 @default.
• W2510157877 cites W2017453705 @default.
• W2510157877 cites W2023238436 @default.
• W2510157877 cites W2023778684 @default.
• W2510157877 cites W2027449023 @default.
• W2510157877 cites W2038061157 @default.
• W2510157877 cites W2039028219 @default.
• W2510157877 cites W2043611538 @default.
• W2510157877 cites W2045997356 @default.
• W2510157877 cites W2057304024 @default.
• W2510157877 cites W2057608998 @default.
• W2510157877 cites W2058553784 @default.
• W2510157877 cites W2060515857 @default.
• W2510157877 cites W2064361803 @default.
• W2510157877 cites W2065459869 @default.
• W2510157877 cites W2068478010 @default.
• W2510157877 cites W2068852923 @default.
• W2510157877 cites W2072351477 @default.
• W2510157877 cites W2074131381 @default.
• W2510157877 cites W2082714048 @default.
• W2510157877 cites W2084074847 @default.
• W2510157877 cites W2084562248 @default.
• W2510157877 cites W2088386461 @default.
• W2510157877 cites W2088772927 @default.
• W2510157877 cites W2089771991 @default.
• W2510157877 cites W2093047307 @default.
• W2510157877 cites W2093825335 @default.
• W2510157877 cites W2098511833 @default.
• W2510157877 cites W2100172364 @default.
• W2510157877 cites W2106586369 @default.
• W2510157877 cites W2108407164 @default.
• W2510157877 cites W2114206069 @default.
• W2510157877 cites W2116869556 @default.
• W2510157877 cites W2123970448 @default.
• W2510157877 cites W2125987139 @default.
• W2510157877 cites W2126780067 @default.
• W2510157877 cites W2127387556 @default.
• W2510157877 cites W2127388725 @default.
• W2510157877 cites W2128940002 @default.
• W2510157877 cites W2131884100 @default.
• W2510157877 cites W2136541538 @default.
• W2510157877 cites W2138427488 @default.
• W2510157877 cites W2138781394 @default.
• W2510157877 cites W2149469368 @default.
• W2510157877 cites W2151394388 @default.
• W2510157877 cites W2154060372 @default.
• W2510157877 cites W2156140279 @default.
• W2510157877 cites W2158076223 @default.
• W2510157877 cites W2159662195 @default.
• W2510157877 cites W2160092129 @default.
• W2510157877 cites W2161673104 @default.
• W2510157877 cites W2166791809 @default.
• W2510157877 cites W2167202160 @default.
• W2510157877 cites W2168272960 @default.
• W2510157877 cites W2168990206 @default.
• W2510157877 cites W2172266256 @default.
• W2510157877 cites W2173185327 @default.
• W2510157877 cites W2183075003 @default.
• W2510157877 cites W2204465283 @default.
• W2510157877 cites W2214441024 @default.
• W2510157877 cites W2225320923 @default.
• W2510157877 cites W2260943715 @default.
• W2510157877 cites W2262375366 @default.
• W2510157877 cites W2278964323 @default.
• W2510157877 cites W2281392042 @default.

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