Abstract
The discovery that coordinated expression of a limited number of genes can reprogram differentiated somatic cells to induced pluripotent stem cells (iPSC) has opened novel possibilities for developing cell-based models of diseases and regenerative medicine utilizing cell reprogramming or cell transplantation. Directed differentiation of iPSCs can potentially generate differentiated cells belonging to any germ layer, including cells with hepatocyte-like morphology and function. Such cells, termed iHeps, can be derived by sequential cell signaling using available information on embryological development or by forced expression of hepatocyte-enriched transcription factors. In addition to the translational aspects of iHeps, the experimental findings have provided insights into the mechanisms of cell plasticity that permit one cell type to transition to another. However, iHeps generated by current methods do not fully exhibit all characteristics of mature hepatocytes, highlighting the need for additional research in this area. Here we summarize the current approaches and achievements in this field and discuss some existing hurdles and emerging approaches for improving iPSC differentiation, as well as maintaining such cells in culture for increasing their utility in disease modeling and drug development.
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References
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126(4):663–676. doi:10.1016/j.cell.2006.07.024
Loh YH, Hartung O, Li H, Guo C, Sahalie JM, Manos PD, et al. Reprogramming of T cells from human peripheral blood. Cell Stem Cell 2010;7(1):15–19. doi:10.1016/j.stem.2010.06.004
Staerk J, Dawlaty MM, Gao Q, Maetzel D, Hanna J, Sommer CA, et al. Reprogramming of human peripheral blood cells to induced pluripotent stem cells. Cell Stem Cell 2010;7(1):20–24. doi:10.1016/j.stem.2010.06.002
Zhou T, Benda C, Duzinger S, Huang Y, Li X, Li Y, et al. Generation of induced pluripotent stem cells from urine. J Am Soc Nephrol 2011;22(7):1221–1228. doi:10.1681/ASN.2011010106
Sauer V, Tchaikovskaya T, Wang X, Li Y, Zhang W, et al. Human urinary epithelial cells as a source of engraftable hepatocyte-like cells using stem cell technology. Cell Transplant 2016. doi:10.3727/096368916X692014
Si-Tayeb K, Idriss S, Champon B, Caillaud A, et al. Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia. Dis Model Mech 2016;9(1):81–90
Sun N, Panetta NJ, Gupta DM, Wilson KD, Lee A, Jia F, et al. Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells. Proc Natl Acad Sci USA 2009;106(37):15720–15725. doi:10.1073/pnas.0908450106
Kim JB, Greber B, Arauzo-Bravo MJ, Meyer J, Park KI, Zaehres H, et al. Direct reprogramming of human neural stem cells by OCT4. Nature 2009;461:643–649. doi:10.1038/nature08436
Liu H, Ye Z, Kim Y, Sharkis S, Jang YY. Generation of endoderm-derived human induced pluripotent stem cells from primary hepatocytes. Hepatology 2010;51(5):1810–1819. doi:10.1002/hep.23626
Aasen T, Raya A, Barrero MJ, Garreta E, Consiglio A, Gonzalez F, et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 2008;26(11):1276–1284. doi:10.1038/nbt.1503
Bar-Nur O, Russ HA, Efrat S, Benvenisty N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell 2011;9(1):17–23. doi:10.1016/j.stem.2011.06.007
Li H, Collado M, Villasante A, Strati K, Ortega S, Canamero M, et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 2009;460:1136–1139. doi:10.1038/nature08290
Haase A, Olmer R, Schwanke K, Wunderlich S, Merkert S, Hess C, et al. Generation of induced pluripotent stem cells from human cord blood. Cell Stem Cell 2009;5(4):434–441. doi:10.1016/j.stem.2009.08.021
Kajiwara M, Aoi T, Okita K, et al. Donor-dependent variations in hepatic differentiation from human-induced pluripotent stem cells. Proc Natl Acad Sci USA 2012;109(31):12538–12543
Kitamura T, Koshino Y, Shibata F, Oki T, Nakajima H, Nosaka T, et al. Retrovirus-mediated gene transfer and expression cloning: powerful tools in functional genomics. Exp Hematol 2003;31(11):1007–1014
Picanco-Castro V, de Sousa Russo-Carbolante EM, Tadeu Covas D. Advances in lentiviral vectors: a patent review. Recent Pat DNA Gene Seq 2012;6(2):82–90
Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, et al. Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 2009;136(5):964–977. doi:10.1016/j.cell.2009.02.013
Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, Hamalainen R, et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 2009;458:766–770. doi:10.1038/nature07863
Roy-Chowdhury J, Horwitz MS. Evolution of adenoviruses as gene therapy vectors. Mol Ther 2002;5:340–344
Stephen SL, Sivanandam VG, Kochanek S. Homologous and heterologous recombination between adenovirus vector DNA and chromosomal DNA. J Gene Med 2008;10(11):1176–1189. doi:10.1002/jgm.1246
Zhou W, Freed CR. Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells. Stem Cells 2009;27(11):2667–2674. doi:10.1002/stem.201
Jia F, Wilson KD, Sun N, Gupta DM, Huang M, Li Z, et al. A nonviral minicircle vector for deriving human iPS cells. Nat Methods 2010;7(3):197–199. doi:10.1038/nmeth.1426
Gonzalez F, Barragan Monasterio M, Tiscornia G, Montserrat Pulido N, Vassena R, Batlle Morera L, et al. Generation of mouse-induced pluripotent stem cells by transient expression of a single nonviral polycistronic vector. Proc Natl Acad Sci USA 2009;106(22):8918–8922. doi:10.1073/pnas.0901471106
Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 2009;324(5928):797–801. doi:10.1126/science.1172482
Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse induced pluripotent stem cells without viral vectors. Science 2008;322(5903):949–953. doi:10.1126/science.1164270
Plews JR, Li J, Jones M, Moore HD, Mason C, Andrews PW, et al. Activation of pluripotency genes in human fibroblast cells by a novel mRNA based approach. PLoS One 2010;5(12):e14397. doi:10.1371/journal.pone.0014397
Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 2010;7(5):618–630. doi:10.1016/j.stem.2010.08.012
Tokusumi T, Iida A, Hirata T, Kato A, Nagai Y, Hasegawa M. Recombinant Sendai viruses expressing different levels of a foreign reporter gene. Virus Res 2002;86(1–2):33–38
Fusaki N, Ban H, Nishiyama A, Saeki K, Hasegawa M. 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. Proc Jpn Acad Ser B Phys Biol Sci 2009;85(8):348–362
Macarthur CC, Fontes A, Ravinder N, Kuninger D, Kaur J, Bailey M, et al. Generation of human-induced pluripotent stem cells by a nonintegrating RNA Sendai virus vector in feeder-free or xeno-free conditions. Stem Cells Int 2012:564612;. doi:10.1155/2012/564612
Nishimura K, Sano M, Ohtaka M, Furuta B, Umemura Y, Nakajima Y, et al. Development of defective and persistent Sendai virus vector: a unique gene delivery/expression system ideal for cell reprogramming. J Biol Chem 2011;286(6):4760–4771. doi:10.1074/jbc.M110.183780
Frankel AD, Pabo CO. Cellular uptake of the tat protein from human immunodeficiency virus. Cell 1988;55(6):1189–1193
Ziegler A, Nervi P, Durrenberger M, Seelig J. The cationic cell-penetrating peptide CPP(TAT) derived from the HIV-1 protein TAT is rapidly transported into living fibroblasts: optical, biophysical, and metabolic evidence. Biochemistry 2005;44(1):138–148. doi:10.1021/bi0491604
Wang Y, Baskerville S, Shenoy A, Babiarz JE, Baehner L, Blelloch R. Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nat Genet 2008;40(12):1478–1483. doi:10.1038/ng.250
Wang Y, Blelloch R. Cell cycle regulation by MicroRNAs in embryonic stem cells. Cancer Res 2009;69:4093–4096. doi:10.1158/0008-5472.CAN-09-0309
Judson RL, Babiarz JE, Venere M, Blelloch R. Embryonic stem cell-specific microRNAs promote induced pluripotency. Nat Biotechnol 2009;27:459–461. doi:10.1038/nbt.1535
Card DA, Hebbar PB, Li L, Trotter KW, Komatsu Y, Mishina Y, et al. Oct4/Sox2-regulated miR-302 targets cyclin D1 in human embryonic stem cells. Mol Cell Biol 2008;28(20):6426–6438. doi:10.1128/MCB.00359-08
Liao B, Bao X, Liu L, Feng S, Zovoilis A, Liu W, et al. MicroRNA cluster 302-367 enhances somatic cell reprogramming by accelerating a mesenchymal-to-epithelial transition. J Biol Chem 2011;286(19):17359–17364. doi:10.1074/jbc.C111.235960
Anokye-Danso F, Trivedi CM, Juhr D, Gupta M, Cui Z, Tian Y, et al. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 2011;8(4):376–388. doi:10.1016/j.stem.2011.03.001
Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, et al. Disease-specific induced pluripotent stem cells. Cell 2008;134(5):877–886. doi:10.1016/j.cell.2008.07.041
Sullivan GJ, Hay DC, Park IH, et al. Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology 2010;51(1):329–335
Takebe T, Sekine K, Enomura M, et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 2013;499:481–484
Nagamoto Y, Tashiro K, Takayama K, et al. The promotion of hepatic maturation of human pluripotent stem cells in 3D co-culture using type I collagen and Swiss 3T3 cell sheets. Biomaterials 2012;33(18):4526–4534
Takayama K, Kawabata K, Nagamoto Y, et al. 3D spheroid culture of hESC/hiPSC-derived hepatocyte-like cells for drug toxicity testing. Biomaterials 2013;34(7):1781–1789
Asgari S, Pournasr B, Salekdeh GH, et al. Induced pluripotent stem cells: a new era for hepatology. J Hepatol 2010;53(4):738–751
Rowland TJ, Miller LM, Blaschke AJ, et al. Roles of integrins in human induced pluripotent stem cell growth on Matrigel and vitronectin. Stem Cells Dev 2010;19(8):1231–1240
Schwartz RE, Fleming HE, Khetani SR, Bhatia SN. Pluripotent stem cell-derived hepatocyte-like cells. Biotechnol Adv 2014;32(2):504–513
Irion S, Nostro MC, Kattman SJ, Keller GM. Directed differentiation of pluripotent stem cells: from developmental biology to therapeutic applications. Cold Spring Harb Symp Quant Biol 2008;73:101–110. doi:10.1101/sqb.2008.73.065
Murry CE, Keller G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 2008;132(4):661–680. doi:10.1016/j.cell.2008.02.008
Han S, Bourdon A, Hamou W, Dziedzic N, Goldman O, Gouon-Evans V. Generation of functional hepatic cells from puripotent stem cells. J Stem Cell Res Ther 2012;1–7. doi:10.4172/2157-7633.S10-008
Touboul T, Hannan NR, Corbineau S, Martinez A, Martinet C, Branchereau S, et al. Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions that recapitulate liver development. Hepatology 2010;51(5):1754–1765. doi:10.1002/hep.23506
Yamanaka Y, Ralston A. Early embryonic cell fate decisions in the mouse. Adv Exp Med Biol 2010;695(01/2010):1–13. doi:10.1007/978-1-4419-7037-4_1
Vallier L, Touboul T, Chng Z, Brimpari M, Hannan N, Millan E, et al. Early cell fate decisions of human embryonic stem cells and mouse epiblast stem cells are controlled by the same signalling pathways. PLoS One 2009;4(6):e6082. doi:10.1371/journal.pone.0006082
Teo AK, Ali Y, Wong KY, Chipperfield H, Sadasivam A, Poobalan Y, et al. Activin and BMP4 synergistically promote formation of definitive endoderm in human embryonic stem cells. Stem Cells 2012;30(4):631–642. doi:10.1002/stem.1022
Toivonen S, Lundin K, Balboa D, Ustinov J, Tamminen K, Palgi J, et al. Activin A and Wnt-dependent specification of human definitive endoderm cells. Exp Cell Res 2013;319(17):2535–2544. doi:10.1016/j.yexcr.2013.07.007
Hansson M, Olesen DR, Peterslund JM, Engberg N, Kahn M, Winzi M, et al. A late requirement for Wnt and FGF signaling during activin-induced formation of foregut endoderm from mouse embryonic stem cells. Dev Biol 2009;330(2):286–304. doi:10.1016/j.ydbio.2009.03.026
Xu X, Browning VL, Odorico JS. Activin, BMP and FGF pathways cooperate to promote endoderm and pancreatic lineage cell differentiation from human embryonic stem cells. Mech Dev 2011;128(7–10):412–427. doi:10.1016/j.mod.2011.08.001
Johansson BM, Wiles MV. Evidence for involvement of activin A and bone morphogenetic protein 4 in mammalian mesoderm and hematopoietic development. Mol Cell Biol 1995;15(1):141–151
Norrman K, Strombeck A, Semb H, Stahlberg A. Distinct gene expression signatures in human embryonic stem cells differentiated towards definitive endoderm at single-cell level. Methods 2013;59(1):59–70. doi:10.1016/j.ymeth.2012.03.030
Kamiya A, Kinoshita T, Miyajima A. Oncostatin M and hepatocyte growth factor induce hepatic maturation via distinct signaling pathways. FEBS Lett 2001;492(1–2):90–94
Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, et al. Scatter factor/hepatocyte growth factor is essential for liver development. Nature 1995;373(6516):699–702. doi:10.1038/373699a0
Duncan SA, Manova K, Chen WS, Hoodless P, Weinstein DC, Bachvarova RF, et al. Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut, and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst. Proc Natl Acad Sci USA 1994;91(16):7598–7602
Gualdi R, Bossard P, Zheng M, Hamada Y, Coleman JR, Zaret KS. Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev 1996;10:1670–1682
Kamiya A, Kinoshita T, Ito Y, Matsui T, Morikawa Y, Senba E, et al. Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer. EMBO J 1999;18(8):2127–2136. doi:10.1093/emboj/18.8.2127
Thomassin H, Flavin M, Espinas ML, Grange T. Glucocorticoid-induced DNA demethylation and gene memory during development. EMBO J 2001;20(8):1974–1983. doi:10.1093/emboj/20.8.1974
Hengstler JG, Brulport M, Schormann W, Bauer A, Hermes M, Nussler AK, et al. Generation of human hepatocytes by stem cell technology: definition of the hepatocyte. Expert Opin Drug Metab Toxicol 2005;1(1):61–74. doi:10.1517/17425255.1.1.61
Wang YM, Chai SC, Brewer CT, Chen T. Pregnane X receptor and drug-induced liver injury. Expert Opin Drug Metab Toxicol 2014;10(11):1521–1532. doi:10.1517/17425255.2014
Avior Y, Levy G, Zimerman M, Kitsberg D, Schwartz R, et al. Microbial-derived lithocholic acid and vitamin K2 drive the metabolic maturation of pluripotent stem cells-derived and fetal hepatocytes. Hepatology 2015;62:265–278
Morelli L. Postnatal development of intestinal microflora as influenced by infant nutrition. J Nutr 2008;138:1791S–1795S
Takayama K, Inamura M, Kawabata K, Tashiro K, Katayama K, Sakurai F, et al. Efficient and directive generation of two distinct endoderm lineages from human ESCs and iPSCs by differentiation stage-specific SOX17 transduction. PLoS One 2011;6(7):e21780. doi:10.1371/journal.pone.0021780PONE-D-11-02464
Inamura M, Kawabata K, Takayama K, Tashiro K, Sakurai F, Katayama K, et al. Efficient generation of hepatoblasts from human ES cells and iPS cells by transient overexpression of homeobox gene HEX. Mol Ther 2011;19(2):400–407. doi:10.1038/mt.2010.241
Takayama K, Inamura M, Kawabata K, Katayama K, Higuchi M, Tashiro K, et al. Efficient generation of functional hepatocytes from human embryonic stem cells and induced pluripotent stem cells by HNF4alpha transduction. Mol Ther 2012;20(1):127–137. doi:10.1038/mt.2011.234
Tahamtani Y, Azarnia M, Farrokhi A, et al. Treatment of human embryonic stem cells with different combinations of priming and inducing factors toward definitive endoderm. Stem Cells Dev 2013;22(9):1419–1432
Siller R, Greenhough S, Naumovska E, Sullivan GJ. Small-molecule-driven hepatocyte differentiation of human pluripotent stem cells. Stem Cell Rep 2015;4(5):939–952
Shan J, Schwartz RE, Ross NT, et al. Identification of small molecules for human hepatocyte expansion and iPS differentiation. Nat Chem Biol 2013;9(8):514–520
Funakoshi N, Duret C, Pascussi JM, Blanc P, Maurel P, Daujat-Chavanieu M, et al. Comparison of hepatic-like cell production from human embryonic stem cells and adult liver progenitor cells: CAR transduction activates a battery of detoxification genes. Stem Cell Rev 2011;7(3):518–531. doi:10.1007/s12015-010-9225-3
Decaens C, Durand M, Grosse B, Cassio D. Which in vitro models could be best used to study hepatocyte polarity? Biol Cell 2008;100(7):387–398. doi:10.1042/BC20070127
Kim Y, Rajagopalan P. 3D hepatic cultures simultaneously maintain primary hepatocyte and liver sinusoidal endothelial cell phenotypes. PLoS One 2010;5:e15456. doi:10.1371/journal.pone.0015456
Stevens KR, Ungrin MD, Schwartz RE, Ng S, Carvalho B, Christine KS, et al. InVERT molding for scalable control of tissue microarchitecture. Nat Commun 2013;4:1847. doi:10.1038/ncomms2853
Baptista PM, Siddiqui MM, Lozier G, Rodriguez SR, Atala A, Soker S. The use of whole organ decellularization for the generation of a vascularized liver organoid. Hepatology 2011;53(2):604–617. doi:10.1002/hep.24067
Uygun BE, Soto-Gutierrez A, Yagi H, Izamis ML, Guzzardi MA, Shulman C, et al. Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med 2010;16:814–820. doi:10.1038/nm.2170
Szkolnicka D, Farnworth SL, Lucendo-Villarin B, Storck C, Zhou W, Iredale JP, et al. Accurate prediction of drug-induced liver injury using stem cell-derived populations. Stem Cells Transl Med 2014;3(2):141–148
Rashid ST, Corbineau S, Hannan N, et al. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Investig 2010;120(9):3127–3136
Tafaleng EN, Chakraborty S, Han B, et al. Induced pluripotent stem cells model personalized variations in liver disease resulting from alpha1-antitrypsin deficiency. Hepatology 2015;62(1):147–157
Choi SM, Kim Y, Shim JS, et al. Efficient drug screening and gene correction for treating liver disease using patient-specific stem cells. Hepatology 2013;57(6):2458–2468
Zhang S, Chen S, Li W, et al. Rescue of ATP7B function in hepatocyte-like cells from Wilson’s disease induced pluripotent stem cells using gene therapy or the chaperone drug curcumin. Hum Mol Genet 2011;20(16):3176–3187
Brown MS, Goldstein JL. Biomedicine. Lowering LDL—not only how low, but how long? Science 2006;311(5768):1721–1723
Cayo MA, Cai J, DeLaForest A, et al. JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia. Hepatology 2012;56(6):2163–2171
Seidah NG, Awan Z, Chretien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res 2014;114:1022–1036
Leung A, Nah SK, Reid W, et al. Induced pluripotent stem cell modeling of multisystemic, hereditary transthyretin amyloidosis. Stem Cell Rep 2013;1(5):451–463
Ng S, Schwartz RE, March S, et al. Human iPSC-derived hepatocyte-like cells support Plasmodium liver-stage infection in vitro. Stem cell reports 2015;4(3):348–359
Yoshida T, Takayama K, Kondoh M, et al. Use of human hepatocyte-like cells derived from induced pluripotent stem cells as a model for hepatocytes in hepatitis C virus infection. Biochem Biophys Res Commun 2011;416(1–2):119–124
Carpentier A, Tesfaye A, Chu V, et al. Engrafted human stem cell-derived hepatocytes establish an infectious HCV murine model. J Clin Investig 2014;124:4953–4964
Dhawan A, Strom SC, Sokal E, Fox IJ. Human hepatocyte transplantation. Methods Mol Biol 2010;640:525–534
Vogel KR, Kennedy AA, Whitehouse LA, Gibson KM. Therapeutic hepatocyte transplant for inherited metabolic disorders: functional considerations, recent outcomes and future prospects. J Inherit Metab Dis 2014;37(2):165–176
Yusa K, Rashid ST, Strick-Marchand H, et al. Targeted gene correction of alpha1-antitrypsin deficiency in induced pluripotent stem cells. Nature 2011;478(7369):391–394
Basma H, Soto-Gutierrez A, Yannam GR, et al. Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology 2009;136(3):990–999
Zhou H, Dong X, Kabarriti R, Chen Y, et al. Single liver lobe repopulation with wildtype hepatocytes using regional hepatic irradiation cures jaundice in Gunn rats. PLoS One 2012;7(10):46775
Chen Y, Li Y, Wang X, Zhang W, et al. Amelioration of hyperbilirubinemia in Gunn rats after transplantation of human induced pluripotent stem cell-derived hepatocytes. Stem Cell Rep 2015;5(1):22–30
Asgari S, Moslem M, Bagheri-Lankarani K, Pournasr B, Miryounesi M, Baharvand H. Differentiation and transplantation of human induced pluripotent stem cell-derived hepatocyte-like cells. Stem Cell Rev 2013;9(4):493–504
Woo DH, et al. Direct and indirect contribution of human embryonic stem cell-derived hepatocyte-like cells to liver repair in mice. Gastroenterology 2012;142(3):602–611
Li HY, et al. Reprogramming induced pluripotent stem cells in the absence of c-Myc for differentiation into hepatocyte-like cells. Biomaterials 2011;32(26):5994–6005
Liu H, Kim Y, Sharkis S, Marchionni L, Jang YY. In vivo liver regeneration potential of human induced pluripotent stem cells from diverse origins. Sci Transl Med 2011;3(82):82ra39
Du Y, et al. Human hepatocytes with drug metabolic function induced from fibroblasts by lineage reprogramming. Cell Stem Cell 2014;14(3):394–403
Zhu S, et al. Mouse liver repopulation with hepatocytes generated from human fibroblasts. Nature 2014;508(7494):93–97
Simeonov KP, Uppal H. Direct reprogramming of human fibroblasts to hepatocyte-like cells by synthetic modified mRNAs. Plos One 2014; e100134
Takebe T, et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 2013;499(7459):481–484
Liu H, Zhu F, Yong J, et al. Generation of induced pluripotent stem cells from adult rhesus monkey fibroblasts. Cell Stem Cell 2008;3(6):587–590
Sourisseau M, Goldman O, He W, et al. Hepatic cells derived from induced pluripotent stem cells of pigtail macaques support hepatitis C virus infection. Gastroenterology 2013;145(5):966 e967–969 e967
Yua Y, Liua H, Ikedad Y, Amiote BP, Rinaldof P, Duncang SA, Nyberg SL. Stem Hepatocyte-like cells differentiated from human induced pluripotent stem cells: relevance to cellular therapies. Cell Res 2012;9(3):196–207. doi:10.1016/j.scr.2012.06.004
Speicher T, Siegenthaler B, Bogorad RL, Ruppert R, Petzold T, Padrissa-Altes S, et al. Knockdown and knockout of β1-integrin in hepatocytes impairs liver regeneration through inhibition of growth factor signalling. Nat Commun 2014;5:3862. doi:10.1038/ncomms4862
Padrissa-Altés S, Bachofner M, Bogorad RL, Pohlmeier L, Rossolini T, Böhm F, Liebisch G, Hellerbrand C, Koteliansky V, Speicher T, Werner S. Control of hepatocyte proliferation and survival by Fgf receptors is essential for liver regeneration in mice. Gut 2015;64(9):1444–1453
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This work was funded in part by the following Grants: 1PO1 DK 096990-01 (to JRC, PD: D. Perlmutter); RO1 DK092469 (to NRC), P30 DK041296-28 (to JRC, A. PD: Wolkoff) R01 DK100490-01A1 (to JRC, PI: DA Shafritz); New York Stem Cell Foundation CO26440 (to JRC); R01 DK064670, R33 CA121051 (to CG).
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Namita Roy-Chowdhury, Xia Wang, Chandan Guha and Jayanta Roy-Chowdhury declare that they have no conflict of interest.
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Roy-Chowdhury, N., Wang, X., Guha, C. et al. Hepatocyte-like cells derived from induced pluripotent stem cells. Hepatol Int 11, 54–69 (2017). https://doi.org/10.1007/s12072-016-9757-y
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DOI: https://doi.org/10.1007/s12072-016-9757-y