Reprogramming cell fates by small molecules

Abstract

Reprogramming cell fates towards pluripotent stem cells and other cell types has revolutionized our understanding of cellular plasticity. During the last decade, transcription factors and microRNAs have become powerful reprogramming factors for modulating cell fates. Recently, many efforts are focused on reprogramming cell fates by non-viral and non-integrating chemical approaches. Small molecules not only are useful in generating desired cell types in vitro for various applications, such as disease modeling and cellbased transplantation, but also hold great promise to be further developed as drugs to stimulate patients’ endogenous cells to repair and regenerate in vivo. Here we will focus on chemical approaches for generating induced pluripotent stem cells, neurons, cardiomyocytes, hepatocytes and pancreatic β cells. Significantly, the rapid and exciting advances in cellular reprogramming by small molecules will help us to achieve the long-term goal of curing devastating diseases, injuries, cancers and aging.

Keywords

reprogramming / small molecules / stem cells / cell fates

References

[1] AddisRC, EpsteinJA (2013) Induced regeneration–the progress and promise of direct reprogramming for heart repair. Nat Med19:829–836

[2] AmbasudhanR, TalantovaM, ColemanR, YuanX, ZhuS, LiptonSA, DingS (2011) Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell9:113–118

[3] AriyachetC, TovaglieriA, XiangG, LuJ, ShahMS, RichmondCA, ZhouQ (2016) Reprogrammed stomach tissue as a renewable source of functional beta cells for blood glucose regulation. Cell Stem Cell18:410–421

[4] BarrilleauxB, KnoepflerP (2011) Transduction of human cells with polymer-complexed ecotropic lentivirus for enhanced biosafety. J Vis Exp53:1–7

[5] CaiazzoM, Dell’AnnoMT, DvoretskovaE, Lazarevic D, TavernaS, LeoD, BroccoliV (2011) Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature476:224–227

[6] CaoN, HuangY, ZhengJ, SpencerCI, ZhangY, FuJ, NieB, XieM, ZhangM, WangH, MaT, XuT, ShiG, SrivastavaD, DingS (2016) Conversion of human fibroblasts into functional cardiomyocytes by small molecules. Science352:1216–1220

[7] ChenJ, LiuJ, YangJ, ChenY, ChenJ, NiS, SongH, ZengL, DingK, PeiD (2011) BMPs functionally replace Klf4 and support efficient reprogramming of mouse fibroblasts by Oct4 alone. Cell Res21:205–212

[8] ChenY, FinkbeinerSR, WeinblattD, EmmettMJ, TameireF, YousefiM, YangC, MaehrR, ZhouQ, ShemerR, DorY, LiC, SpenceJR, StangerBZ (2014) De novo formation of insulin-producing “neobeta cell islets” from intestinal crypts. Cell Rep6:1046–1058

[9] ChenG, WernigM, BerningerB, NakafukuM, ParmarM, ZhangCL (2015) In vivo reprogramming for brain and spinal cord repair. eNeuro2:e0106–15

[10] ChengL, HuW, QiuB, ZhaoJ, YuY, GuanW, WangM, YangW, PeiG (2014) Generation of neural progenitor cells by chemical cocktails and hypoxia. Cell Res24:665–679

[11] DuY, WangJ, JiaJ, SongN, XiangC, XuJ, HouZ, SuX, LiuB, JiangT, ZhaoD, SunY, ShuJ, GuoQ, YinM, SunD, LuS, ShiY, DengH (2014) Human hepatocytes with drug metabolic function induced from fibroblasts by lineage reprogramming. Cell Stem Cell14:394–403

[12] FuJ, StoneNR, LiuL, SpencerCI, QianL, HayashiY, Delgado-OlguinP, DingS, BruneauBG, SrivastavaD (2013) Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state. Stem Cell Reports1:235–247

[13] FuY, HuangC, XuX, GuH, YeY, JiangC, QiuZ, XieX (2015) Direct reprogramming of mouse fibroblasts into cardiomyocytes with chemical cocktails. Cell Res25:1013–1024

[14] FusakiN, BanH, NishiyamaA, SaekiK, HasegawaM (2009) Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proce Jpn Acad Ser B85:348–362

[15] GonzalezF, BoueS, Izpisua BelmonteJC (2011) Methods for making induced pluripotent stem cells: reprogramming a la carte. Nat Rev Genet12:231–242

[16] GuoZ, ZhangL, WuZ, ChenY, WangF, ChenG (2014) In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Cell Stem Cell14:188–202

[17] GurdonJB (1962) The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morphol10:622–640

[18] HockemeyerD, JaenischR (2016) Induced pluripotent stem cells meet genome editing. Cell Stem Cell18:573–586

[19] HouP, LiY, ZhangX, LiuC, GuanJ, LiH, ZhaoT, YeJ, YangW, LiuK, GeJ, XuJ, ZhangQ, ZhaoY, DengH (2013) Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science341:651–654

[20] HuW, QiuB, GuanW, WangQ, WangM, LiW, GaoL, ShenL, HuangY, XieG, ZhaoH, JinY, TangB, YuY, ZhaoJ, PeiG (2015) Direct conversion of normal and Alzheimer’s disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell17:204–212

[21] HuangP, HeZ, JiS, SunH, XiangD, LiuC, HuY, WangX, HuiL (2011) Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature475:386–389

[22] HuangP, ZhangL, GaoY, HeZ, YaoD, WuZ, CenJ, ChenX, LiuC, HuY, LaiD, HuZ, ChenL, ZhangY, ChengX, MaX, PanG, WangX, HuiL (2014) Direct reprogramming of human fibroblasts to functional and expandable hepatocytes. Cell Stem Cell14:370–384

[23] HuangfuD, MaehrR, GuoW, EijkelenboomA, SnitowM, ChenAE, MeltonDA (2008) Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol26:795–797

[24] IchidaJK, BlanchardJ, LamK, SonEY, ChungJE, EgliD, LohKM, CarterAC, Di GiorgioFP, KoszkaK, HuangfuD, AkutsuH, LiuDR, RubinLL, EgganK (2009) A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell5:491–503

[25] IedaM (2016) Heart development, diseases, and regeneration- new approaches from innervation, fibroblasts, and reprogramming. Circ J80:2081–2088

[26] IedaM, FuJ, Delgado-OlguinP, VedanthamV, HayashiY, BruneauBG, SrivastavaD (2010) Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell142:375–386

[27] IfkovitsJL, AddisRC, EpsteinJA, GearhartJD (2014) Inhibition of TGFbeta signaling increases direct conversion of fibroblasts to induced cardiomyocytes. PLoS One9:e89678

[28] IslasJF, LiuY, WengK-C, RobertsonMJ, ZhangS, PrejusaA, HargerJ, TikhomirovaD, ChopraM, IyerD, MercolaM, OshimaRG, WillersonJT, PotamanVN, SchwartzRJ (2012) Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors. Proc Natl Acad Sci USA109:13016–13021

[29] JayawardenaTM, EgemnazarovB, FinchEA, ZhangL, PayneJA, PandyaK, ZhangZ, RosenbergP, MirotsouM, DzauVJ (2012) MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res110:1465–1473

[30] KimKS (2011) Converting human skin cells to neurons: a new tool to study and treat brain disorders?Cell Stem Cell9:179–181

[31] KimD, KimCH, MoonJI, ChungYG, ChangMY, HanBS, KoS, YangE, ChaKY, LanzaR, KimKS (2009) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell4:472–476

[32] KimJ, EfeJA, ZhuS, TalantovaM, YuanX, WangS, LiptonSA, ZhangK, DingS (2011) Direct reprogramming of mouse fibroblasts to neural progenitors. Proc Natl Acad Sci USA108:7838–7843

[33] KimJ, KimKP, LimKT, LeeSC, YoonJ, SongG, HwangSI, SchölerHR, CantzT, HanDW (2015) Generation of integration-free induced hepatocyte-like cells from mouse fibroblasts. Sci Rep5:15706

[34] LalitPA, SalickMR, NelsonDO, SquirrellJM, ShaferCM, PatelNG, SaeedI, SchmuckEG, MarkandeyaYS, WongR, LeaMR, EliceiriKW, HackerTA, CroneWC, KybaM, GarryDJ, StewartR, ThomsonJA, DownsKM, LyonsGE, KampTJ (2016) Lineage reprogramming of fibroblasts into proliferative induced cardiac progenitor cells by defined factors. Cell Stem Cell18:354–367

[35] LeeJ, SugiyamaT, LiuY, WangJ, GuX, LeiJ, MarkmannJF, MiyazakiS, MiyazakiJ, SzotGL, BottinoR, KimSK (2013) Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells. Elife2:e00940

[36] LefebvreB, BelaichS, LongueJ, VandewalleB, OberholzerJ, GmyrV, PattouF, Kerr-ConteJ (2010) 5’-AZA induces Ngn3 expression and endocrine differentiation in the PANC-1 human ductal cell line. Biochem Biophys Res Commun391:305–309

[37] LiH, ChenG (2016) In vivo reprogramming for CNS repair: regenerating neurons from endogenous glial cells. Neuron91:728–738

[38] LiW, ZhouH, AbujarourR, ZhuS, Young JooJ, LinT, HaoE, SchölerHR, HayekA, DingS (2009) Generation of humaninduced pluripotent stem cells in the absence of exogenous Sox2. Stem Cells27:2992–3000

[39] LiR, LiangJ, NiS, ZhouT, QingX, LiH, HeW, ChenJ, LiF, ZhuangQ, QinB, XuJ, LiW, YangJ, GanY, QinD, FengS, SongH, YangD, ZhangB, ZengL, LaiL, EstebanMA, PeiD (2010) Amesenchymalto-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell7:51–63

[40] LiY, ZhangQ, YinX, YangW, DuY, HouP, GeJ, LiuC, ZhangW, ZhangX, WuY, LiH, LiuK, WuC, SongZ, ZhaoY, ShiY, DengH (2011) Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Res21:196–204

[41] LiH, ZhouH, WangD, QiuJ, ZhouY, LiX, RosenfeldMG, DingS, FuX (2012) Versatile pathway-centric approach based on highthroughput sequencing to anticancer drug discovery. Proc Natl Acad Sci USA109:4609–4614

[42] LiW, Cavelti-WederC, ZhangY, ClementK, DonovanS, GonzalezG, ZhuJ, StemannM, XuK, HashimotoT, YamadaT, NakanishiM, ZhangY, ZengS, GiffordD, MeissnerA, WeirG, ZhouQ (2014a) Long-term persistence and development of induced pancreatic beta cells generated by lineage conversion of acinar cells. Nat Biotechnol32:1223–1230

[43] LiW, NakanishiM, ZumstegA, ShearM, WrightC, MeltonDA, ZhouQ (2014b) In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes. Elife3:e01846

[44] LiX, ZuoX, JingJ, MaY, WangJ, LiuD, ZhuJ, DuX, XiongL, DuY, XuJ, XiaoX, WangJ, ChaiZ, ZhaoY, DengH (2015) Smallmolecule-driven direct reprogramming of mouse fibroblasts into functional neurons. Cell Stem Cell17:195–203

[45] LimKT, LeeSC, GaoY, KimKP, SongG, AnSY, AdachiK, JangYJ, KimJ, OhKJ, KwakTH, HwangSI, YouJS, KoK, KooSH, SharmaAD, KimJH, HuiL, CantzT, SchölerHR, HanDW (2016) Small molecules facilitate single factor-mediated hepatic reprogramming. Cell Rep15:814–829

[46] LyssiotisCA, ForemanRK, StaerkJ, GarciaM, MathurD, MarkoulakiS, HannaJ, LairsonLL, CharetteBD, BouchezLC, BollongM, KunickC, BrinkerA, ChoCY, SchultzPG, JaenischR (2009) Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4. Proc Natl Acad Sci USA106:8912–8917

[47] MinamiK, OkunoM, MiyawakiK, OkumachiA, IshizakiK, OyamaK, KawaguchiM, IshizukaN, IwanagaT, SeinoS (2005) Lineage tracing and characterization of insulin-secreting cells generated from adult pancreatic acinar cells. Proc Natl Acad Sci USA102:15116–15121

[48] MuraokaN, YamakawaH, MiyamotoK, SadahiroT, UmeiT, IsomiM, NakashimaH, AkiyamaM, WadaR, InagawaK, NishiyamaT, KanedaR, FukudaT, TakedaS, TohyamaS, HashimotoH, KawamuraY, GoshimaN, AebaR, YamagishiH, FukudaK, IedaM (2014) MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures. EMBO J33:1565–1581

[49] NamYJ, SongK, LuoX, DanielE, LambethK, WestK, HillJA, DiMaioJM, BakerLA, Bassel-DubyR, OlsonEN (2013) Reprogramming of human fibroblasts toward a cardiac fate. Proc Natl Acad Sci USA110:5588–5593

[50] NiuW, ZangT, ZouY, FangS, SmithDK, BachooR, ZhangCL (2013) In vivo reprogramming of astrocytes to neuroblasts in the adult brain. Nat Cell Biol15:1164–1175

[51] PangZ, YangN, VierbuchenT, OstermeierA, FuentesDR, YangT, WernigM (2011) Induction of human neuronal cells by defined transcription factors. Nature476:220–223

[52] PournasrB, Asghari-VostikolaeeMH, BaharvandH (2015) Transcription factor-mediated reprograming of fibroblasts to hepatocyte-like cells. Eur J Cell Biol94:603–610

[53] QianL, HuangY, SpencerCI, FoleyA, VedanthamV, LiuL, SrivastavaD (2012) In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature485:593–598

[54] RezvaniM, Espanol-SunerR, MalatoY, DumontL, GrimmAA, KienleE, WillenbringH (2016) In vivo hepatic reprogramming of myofibroblasts with aav vectors as a therapeutic strategy for liver fibrosis. Cell Stem Cell18:809–816

[55] RieW, MuraokaN, InagawaK, YamakawaH, MiyamotoK, SadahiroT, UmeiT, KanedaR, SuzukiT, KamiyaK, TohyamaS (2013) Induction of human cardiomyocyte-like cells from fibroblasts by defined factors. Proc Natl Acad Sci USA110:12667–12672

[56] RingKL, TongLM, BalestraME, JavierR, Andrews-ZwillingY, LiG, WalkerD, ZhangWR, KreitzerAC, HuangY (2012) Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell Stem Cell11:100–109

[57] SekiyaS, SuzukiA (2011) Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature475:390–393

[58] ShalemO, SanjanaNE, HartenianE, ShiX, ScottDA, MikkelsenTS, HecklD, EbertBL, RootDE, DoenchJG, ZhangF (2014) Genome-scale CRISPR-Cas9 knockout screening in human cells. Science343:84–87

[59] ShiY, DespontsC, DoJT, HahmHS, ScholerHR, DingS (2008) Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell3:568–574

[60] SimeonovKP, UppalH (2014) Direct reprogramming of human fibroblasts to hepatocyte-like cells by synthetic modified mRNAs. PLoS One9:e100134

[61] SonEY, IchidaJK, WaingerBJ, TomaJS, RafuseVF, WoolfCJ, EgganK (2011) Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell9:205–218

[62] SongK, NamYJ, LuoX, QiX, TanW, HuangG, AcharyaA, SmithCL, TallquistMD, NeilsonEG, HillJA, Bassel-DubyR, OlsonEN (2012) Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature485:599–604

[63] SongG, PacherM, BalakrishnanA, YuanQ, TsayHC, YangD, ReetzJ, BrandesS, DaiZ, PützerBM, Araúzo-BravoMJ, SteinemannD, LueddeT, SchwabeRF, MannsMP, SchölerHR, SchambachA, CantzT, OttM, SharmaAD (2016) Direct reprogramming of hepatic myofibroblasts into hepatocytes in vivo attenuates liver fibrosis. Cell Stem Cell18:797–808

[64] TadaM, TadaT, LefebvreL, BartonSC, SuraniMA (1997) Embryonic germ cells induce epigenetic reprogramming of somatic nucleus in hybrid cells. EMBO J16:6510–6520

[65] TakahashiK, YamanakaS (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell126:663–676

[66] TakahashiK, YamanakaS (2016) A decade of transcription factormediated reprogramming to pluripotency. Nat Rev Mol Cell Biol17:183–193

[67] VierbuchenT, OstermeierA, PangZ, KokubuY, SudhofTC, WernigM (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature463:1035–1041

[68] WangH, CaoN, SpencerCI, NieB, MaT, XuT, ZhangY, WangX, SrivastavaD, DingS (2014) Small molecules enable cardiac reprogramming of mouse fibroblasts with a single factor, Oct4. Cell Rep6:951–960

[69] WangY, QinJ, WangS, ZhangW, DuanJ, ZhangJ, WangX, YanF, ChangM, LiuX, FengB, LiuJ, PeiX (2016) Conversion of human gastric epithelial cells to multipotent endodermal progenitors using defined small molecules. Cell Stem Cell19:449–461

[70] WarrenL,ManosPD, AhfeldtT, LohYH, LiH, LauF, EbinaW, MandalPK, SmithZD, MeissnerA, DaleyGQ, BrackAS, CollinsJJ, CowanC, SchlaegerTM, RossiDJ (2010) Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell7:618–630

[71] WenL, TangF (2016) Single-cell sequencing in stem cell biology. Genome Biol17:71

[72] YamakawaH, MuraokaN,MiyamotoK, SadahiroT, IsomiM, HaginiwaS, KojimaH, UmeiT, AkiyamaM,KuishiY, KurokawaJ, FurukawaT, FukudaK, IedaM (2015) Fibroblast growth factors and vascular endothelial growth factor promote cardiac reprogramming under defined conditions. Stem Cell Reports5:1128–1142

[73] YangH, ZhangL, AnJ, ZhangQ, LiuC, HeB, HaoD (2016) MicroRNAmediated reprogramming of somatic cells into neural stem cells or neurons. Mol Neurobiol.

[74] YooAS, SunAX, LiL, ShcheglovitovA, PortmannT, LiY, Lee-MesserC, DolmetschRE, TsienRW, CrabtreeGR (2011) MicroRNA-mediated conversion of human fibroblasts to neurons. Nature476:228–231

[75] YuB, HeZ, YouP, HanQ, XiangD, ChenF, WangM, LiuC, LinX, BorjiginU, ZiX, LiJ, ZhuH, LiW, HanC, WangensteenKJ, ShiY, HuiL, WangX, HuY (2013) Reprogramming fibroblasts into bipotential hepatic stem cells by defined factors. Cell Stem Cell13:328–340

[76] YuanX, WanH, ZhaoX, ZhuS, ZhouQ, DingS (2011) Brief report: combined chemical treatment enables Oct4-induced reprogramming from mouse embryonic fibroblasts. Stem Cells29:549–553

[77] YuanY, HartlandK, BoskovicZ, WangY, WalpitaD, LysyPA, ZhongC, YoungDW, KimYK, TollidayNJ, SokalEM, SchreiberSL, WagnerBK (2013) A small-molecule inducer of PDX1 expression identified by high-throughput screening. Chem Biol20:1513–1522

[78] ZhangL, YinJ, YehH, MaN, LeeG, ChenX, WangY, LinL, ChenL, JinP, WuG, ChenG (2015) Small molecules efficiently reprogram human astroglial cells into functional neurons. Cell Stem Cell17:735–747

[79] ZhangM, LinY, SunY, ZhuS, ZhengJ, LiuK, CaoN, LiK, HuangY, DingS (2016a) Pharmacological reprogramming of fibroblasts into neural stem cells by signaling-directed transcriptional activation. Cell Stem Cell18:653–667

[80] ZhangY, CaoN, HuangY, SpencerCI, FuJ, YuC, LiuK, NieB, XuT, LiK, XuS, BruneauBG, SrivastavaD, DingS (2016b) Expandable cardiovascular progenitor cells reprogrammed from fibroblasts. Cell Stem Cell18:368–381

[81] ZhaoY, LondonoP, CaoY, SharpeEJ, ProenzaC, O’RourkeR, JonesKL, JeongMY, WalkerLA, ButtrickPM, McKinseyTA, SongK (2015a) High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling. Nat Commun6: 8243

[82] ZhaoY, ZhaoT, GuanJ, ZhangX, FuY, YeJ, ZhuJ, MengG, GeJ, YangS, ChengL, DuY, ZhaoC, WangT, SuL, YangW, DengH (2015b) A XEN-like state bridges somatic cells to pluripotency during chemical reprogramming. Cell163:1678–1691

[83] ZhouW, FreedCR (2009) Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells. Stem Cells27:2667–2674

[84] ZhouQ, TripathiP (2012) How to remake a fibroblast into a neural stem cell. Cell Stem Cell10:347–348

[85] ZhouQ, BrownJ, KanarekA, RajagopalJ, MeltonDA (2008) In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature455:627–632

[86] ZhouY, WangL, VaseghiHR, LiuZ, LuR, AlimohamadiS, YinC, FuJ, WangG, LiuJ, QianL (2016) Bmi1 is a key epigenetic barrier to direct cardiac reprogramming. Cell Stem Cell18:382–395

[87] ZhuS, LiW, ZhouH, WeiW, AmbasudhanR, LinT, KimJ, ZhangK, DingS (2010) Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell7:651–655

[88] ZhuS, AmbasudhanR, SunW, KimHJ, TalantovaM, WangX, ZhangM, ZhangY, LaurentT, ParkerJ, KimHS, ZarembaJD, SaleemS, Sanz-BlascoS, MasliahE, McKercherSR, ChoYS, LiptonSA, KimJ, DingS (2014a) Small molecules enable OCT4-mediated direct reprogramming into expandable human neural stem cells. Cell Res24:126–129

[89] ZhuS, RezvaniM, HarbellJ, MattisAN, WolfeAR, BenetLZ, WillenbringH, DingS (2014b) Mouse liver repopulation with hepatocytes generated from human fibroblasts. Nature508:93–97

[90] ZhuS, WangH, DingS (2015) Reprogramming fibroblasts toward cardiomyocytes, neural stem cells and hepatocytes by cell activation and signaling-directed lineage conversion. Nat Protoc10:959–973

[91] ZhuS, RussHA, WangX, ZhangM, MaT, XuT, TangS, HebrokM, DingS (2016) Human pancreatic beta-like cells converted from fibroblasts. Nat Commun7:10080

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