The Use of Induced Pluripotent Stem Cells for the Study and Treatment of Liver Diseases

Marc C. Hansel1, Julio C. Davila2, Massoud Vosough3, Roberto Gramignoli3, Kristen J. Skvorak4, Kenneth Dorko5, Fabio Marongiu6, William Blake7, Stephen C. Strom3

1 McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania, 2 Department of Biochemistry, University of Puerto Rico School of Medicine, Medical Sciences Campus, San Juan, Puerto Rico, 3 Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden, 4 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 5 Department of Pharmacology, Toxicology and Therapeutics, Kansas University Medical Center, Kansas City, Kansas, 6 Department of Biomedical Sciences, Section of Experimental Pathology, Unit of Experimental Medicine, University of Cagliari, Cagliari, 7 Genetically Modified Models Center of Emphasis, Pfizer, Groton, Connecticut
Publication Name:  Current Protocols in Toxicology
Unit Number:  Unit 14.13
DOI:  10.1002/0471140856.tx1413s67
Online Posting Date:  February, 2016
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Liver disease is a major global health concern. Liver cirrhosis is one of the leading causes of death in the world and currently the only therapeutic option for end‐stage liver disease (e.g., acute liver failure, cirrhosis, chronic hepatitis, cholestatic diseases, metabolic diseases, and malignant neoplasms) is orthotropic liver transplantation. Transplantation of hepatocytes has been proposed and used as an alternative to whole organ transplant to stabilize and prolong the lives of patients in some clinical cases. Although these experimental therapies have demonstrated promising and beneficial results, their routine use remains a challenge due to the shortage of donor livers available for cell isolation, variable quality of those tissues, the potential need for lifelong immunosuppression in the transplant recipient, and high costs. Therefore, new therapeutic strategies and more reliable clinical treatments are urgently needed. Recent and continuous technological advances in the development of stem cells suggest they may be beneficial in this respect. In this review, we summarize the history of stem cell and induced pluripotent stem cell (iPSC) technology in the context of hepatic differentiation and discuss the potential applications the technology may offer for human liver disease modeling and treatment. This includes developing safer drugs and cell‐based therapies to improve the outcomes of patients with currently incurable health illnesses. We also review promising advances in other disease areas to highlight how the stem cell technology could be applied to liver diseases in the future. © 2016 by John Wiley & Sons, Inc.

Keywords: disease‐specific induced pluripotent stem cells; cell therapy; metabolic liver disease; liver disease; regenerative medicine; cell transplantation; human liver disease modeling

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Table of Contents

  • Introduction
  • General Stem Cell Information: From ESCs to iPSCs
  • iPSC Derivation: Various Methods and Cell Sources
  • Differentiation to Hepatocytes
  • Epigenetic Memory, Donor Differences, and Cell Source Influencing iPSC Differentiation Potentials
  • In Vitro and In Vivo Liver Disease Modeling with iPSCs and Genetic Correction
  • Patient‐Specific iPSCs: Are They Clinically Relevant?
  • Challenges of iPSC Applications and the Path Moving Forward
  • Overall Conclusions
  • Literature Cited
  • Figures
  • Tables
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Literature Cited

Literature Cited
  Aasen, T., Raya, A., Barrero, M.J., Garreta, E., Consiglio, A., Gonzalez, F., Vassena, R., Bilic, J., Pekarik, V., Tiscornia, G., Edel, M., Boue, S., and Izpisua Belmonte, J.C. 2008. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat. Biotechnol. 26:1276‐1284. doi: 10.1038/nbt.1503.
  Agarwal, S., Holton, K.L., and Lanza, R. 2008. Efficient differentiation of functional hepatocytes from human embryonic stem cells. Stem Cells 26:1117‐1127. doi: 10.1634/stemcells.2007‐1102.
  Andrews, P.W., Cavanagro, J., Deans, R., Feigel, E., Horowitz, E., Keating, A., Rao, M., Turner, M., Wilmut, I., and Yamanaka, S. 2014. Harmonizing standards for producing clinical‐grade therapies from pluripotent stem cells. Nat. Biotechnol. 32:724‐726. doi: 10.1038/nbt.2973.
  Angel, M. and Yanik, M.F. 2010. Innate immune suppression enables frequent transfection with RNA encoding reprogramming proteins. PLoS One 5:e11756. doi: 10.1371/journal.pone.0011756.
  Anonymous. 2014. Yamanaka announces plan to establish global iPS cell bank. The Asahi Shimbun.
  Aoi, T., Yae, K., Nakagawa, M., Ichisaka, T., Okita, K., Takahashi, K., Chiba, T., and Yamanaka, S. 2008. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 321:699‐702. doi: 10.1126/science.1154884.
  Arcidiacono, J.A., Blair, J.W., and Benton, K.A. 2012. US Food and Drug Administration international collaborations for cellular therapy product regulation. Stem Cell Res. Ther. 3:38. doi: 10.1186/scrt129.
  Asakura, A. 2014. Grand challenges in the field of stem cell research. Front. Cell Dev. Biol. 2:2. doi: 10.3389/fcell.2014.00002.
  Asgari, S., Moslem, M., Bagheri‐Lankarani, K., Pournasr, B., Miryounesi, M., and Baharvand, H. 2013. Differentiation and transplantation of human induced pluripotent stem cell‐derived hepatocyte‐like cells. Stem. Cell Rev. 9:493‐504. doi: 10.1007/s12015‐011‐9330‐y.
  Azuma, H., Paulk, N., Ranade, A., Dorrell, C., Al‐Dhalimy, M., Ellis, E., Strom, S., Kay, M.A., Finegold, M., and Grompe, M. 2007. Robust expansion of human hepatocytes in Fah‐/‐/Rag2‐/‐/Il2rg‐/‐ mice. Nat. Biotechnol. 25:903‐910. doi: 10.1038/nbt1326.
  Ban, H., Nishishita, N., Fusaki, N., Tabata, T., Saeki, K., Shikamura, M., Takada, N., Inoue, M., Hasegawa, M., Kawamata, S., and Nishikawa, S. 2011. Efficient generation of transgene‐free human induced pluripotent stem cells (iPSCs) by temperature‐sensitive Sendai virus vectors. Proc. Natl. Acad. Sci. U. S. A. 108:14234‐14239. doi: 10.1073/pnas.1103509108.
  Barrett, R., Ornelas, L., Yeager, N., Mandefro, B., Sahabian, A., Lenaeus, L., Targan, S.R., Svendsen, C.N., and Sareen, D. 2014. Reliable generation of induced pluripotent stem cells from human lymphoblastoid cell lines. Stem Cells Transl. Med. 3:1429‐1434. doi: 10.5966/sctm.2014‐0121.
  Basma, H., Soto‐Gutierrez, A., Yannam, G.R., Liu, L., Ito, R., Yamamoto, T., Ellis, E., Carson, S.D., Sato, S., Chen, Y., Muirhead, D., Navarro‐Alvarez, N., Wong, R.J., Roy‐Chowdhury, J., Platt, J.L., Mercer, D.F., Miller, J.D., Strom, S.C., Kobayashi, N., and Fox, I.J. 2009. Differentiation and transplantation of human embryonic stem cell‐derived hepatocytes. Gastroenterology 136:990‐999 e994. doi: 10.1053/j.gastro.2008.10.047.
  Baxter, M.A., Rowe, C., Alder, J., Harrison, S., Hanley, K.P., Park, B.K., Kitteringham, N.R., Goldring, C.E., and Hanley, N.A. 2010. Generating hepatic cell lineages from pluripotent stem cells for drug toxicity screening. Stem Cell Res. 5:4‐22. doi: 10.1016/j.scr.2010.02.002.
  Ben‐David, U. and Benvenisty, N. 2014. Chemical ablation of tumor‐initiating human pluripotent stem cells. Nat. Protoc. 9:729‐740. doi: 10.1038/nprot.2014.050.
  Bhutani, N., Brady, J.J., Damian, M., Sacco, A., Corbel, S.Y., and Blau, H.M. 2010. Reprogramming towards pluripotency requires AID‐dependent DNA demethylation. Nature 463:1042‐1047. doi: 10.1038/nature08752.
  Bone, H.K., Nelson, A.S., Goldring, C.E., Tosh, D., and Welham, M.J. 2011. A novel chemically directed route for the generation of definitive endoderm from human embryonic stem cells based on inhibition of GSK‐3. J. Cell Sci. 124:1992‐2000. doi: 10.1242/jcs.081679.
  Borowiak, M., Maehr, R., Chen, S., Chen, A.E., Tang, W., Fox, J.L., Schreiber, S.L., and Melton, D.A. 2009. Small molecules efficiently direct endodermal differentiation of mouse and human embryonic stem cells. Cell Stem. Cell 4:348‐358. doi: 10.1016/j.stem.2009.01.014.
  Bukong, T.N., Lo, T., Szabo, G., and Dolganiuc, A. 2012. Novel developmental biology‐based protocol of embryonic stem cell differentiation to morphologically sound and functional yet immature hepatocytes. Liver Int. 32:732‐741. doi: 10.1111/j.1478‐3231.2011.02743.x.
  Cai, J., DeLaForest, A., Fisher, J., Urick, A., Wagner, T., Twaroski, K., Cayo, M., Nagaoka, M., and Duncan, S.A. 2008. Protocol for directed differentiation of human pluripotent stem cells toward a hepatocyte fate. In: StemBook [Internet]. Cambridge (MA): Harvard Stem Cell Institute; 2008‐. Available from:
  Cai, J., Zhao, Y., Liu, Y., Ye, F., Song, Z., Qin, H., Meng, S., Chen, Y., Zhou, R., Song, X., Guo, Y., Ding, M., and Deng, H. 2007. Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology 45:1229‐1239. doi: 10.1002/hep.21582.
  Cai, J., Li, W., Su, H., Qin, D., Yang, J., Zhu, F., Xu, J., He, W., Guo, X., Labuda, K., Peterbauer, A., Wolbank, S., Zhong, M., Li, Z., Wu, W., So, K.F., Redl, H., Zeng, L., Esteban, M.A., and Pei, D. 2010. Generation of human induced pluripotent stem cells from umbilical cord matrix and amniotic membrane mesenchymal cells. J. Biol. Chem. 285:11227‐11234. doi: 10.1074/jbc.M109.086389.
  Cantz, T., Sharma, A.D., and Ott, M. 2015. Concise review: Cell therapies for hereditary metabolic liver diseases‐concepts, clinical results, and future developments. Stem Cells 33:1055‐1062. doi: 10.1002/stem.1920.
  Carbery, I.D., Ji, D., Harrington, A., Brown, V., Weinstein, E.J., Liaw, L., and Cui, X. 2010. Targeted genome modification in mice using zinc‐finger nucleases. Genetics 186:451‐459. doi: 10.1534/genetics.110.117002.
  Carey, B.W., Markoulaki, S., Hanna, J.H., Faddah, D.A., Buganim, Y., Kim, J., Ganz, K., Steine, E.J., Cassady, J.P., Creyghton, M.P., Welstead, G.G., Gao, Q., and Jaenisch, R. 2011. Reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells. Cell Stem Cell 9:588‐598. doi: 10.1016/j.stem.2011.11.003.
  Chan, E.M., Ratanasirintrawoot, S., Park, I.H., Manos, P.D., Loh, Y.H., Huo, H., Miller, J.D., Hartung, O., Rho, J., Ince, T.A., Daley, G.Q., and Schlaeger, T.M. 2009. Live cell imaging distinguishes bona fide human iPS cells from partially reprogrammed cells. Nat. Biotechnol. 27:1033‐1037. doi: 10.1038/nbt.1580.
  Chen, Y.F., Tseng, C.Y., Wang, H.W., Kuo, H.C., Yang, V.W., and Lee, O.K. 2012. Rapid generation of mature hepatocyte‐like cells from human induced pluripotent stem cells by an efficient three‐step protocol. Hepatology 55:1193‐1203. doi: 10.1002/hep.24790.
  Cheng, R., Peng, J., Yan, Y., Cao, P., Wang, J., Qiu, C., Tang, L., Liu, D., Jin, J., Huang, X., He, F., and Zhang, P. 2014. Efficient gene editing in adult mouse livers via adenoviral delivery of CRISPR/Cas9. FEBS Lett. 588:3954‐3958. doi: 10.1016/j.febslet.2014.09.008.
  Choi, K.D., Yu, J., Smuga‐Otto, K., Salvagiotto, G., Rehrauer, W., Vodyanik, M., Thomson, J., and Slukvin, I. 2009. Hematopoietic and Endothelial Differentiation of Human Induced Pluripotent Stem Cells. Stem. Cells 27:559‐567. doi: 10.1002/stem.20080922.
  Choi, S.M., Kim, Y., Shim, J.S., Park, J.T., Wang, R.H., Leach, S.D., Liu, J.O., Deng, C., Ye, Z., and Jang, Y.Y. 2013. Efficient drug screening and gene correction for treating liver disease using patient‐specific stem cells. Hepatology 57:2458‐2468. doi: 10.1002/hep.26237.
  Choi, Y.J., Lin, C.P., Ho, J.J., He, X., Okada, N., Bu, P., Zhong, Y., Kim, S.Y., Bennett, M.J., Chen, C., Ozturk, A., Hicks, G.G., Hannon, G.J., and He, L. 2011. miR‐34 miRNAs provide a barrier for somatic cell reprogramming. Nat. Cell Biol. 13:1353‐1360. doi: 10.1038/ncb2366.
  Cooper, O., Hargus, G., Deleidi, M., Blak, A., Osborn, T., Marlow, E., Lee, K., Levy, A., Perez‐Torres, E., Yow, A., and Isacson, O. 2010. Differentiation of human ES and Parkinson's disease iPS cells into ventral midbrain dopaminergic neurons requires a high activity form of SHH, FGF8a and specific regionalization by retinoic acid. Mol. Cell Neurosci. 45:258‐266. doi: 10.1016/j.mcn.2010.06.017.
  D'Amour, K.A., Agulnick, A.D., Eliazer, S., Kelly, O.G., Kroon, E., and Baetge, E.E. 2005. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat. Biotechnol. 23:1534‐1541. doi: 10.1038/nbt1163.
  Davila, J.C., Donaldson, D.B., Engle, S.J., Pryor, H.I., and Vacanti, J.P. 2009. Stem Cell Technology for Embryotoxicity and Hepatotoxicity Evaluation. In Drug Efficacy, Safety, and Biologics Discovery: Emerging Technologies and Tools (S. Ekins, and J. Xu, eds.) pp. 175‐213. John Wiley & Sons, New Jersey.
  de Almeida, P.E., Meyer, E.H., Kooreman, N.G., Diecke, S., Dey, D., Sanchez‐Freire, V., Hu, S., Ebert, A., Odegaard, J., Mordwinkin, N.M., Brouwer, T.P., Lo, D., Montoro, D.T., Longaker, M.T., Negrin, R.S., and Wu, J.C. 2014. Transplanted terminally differentiated induced pluripotent stem cells are accepted by immune mechanisms similar to self‐tolerance. Nat. Commun. 5:3903.
  DeLaForest, A., Nagaoka, M., Si‐Tayeb, K., Noto, F.K., Konopka, G., Battle, M.A., and Duncan, S.A. 2011. HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells. Development 138:4143‐4153. doi: 10.1242/dev.062547.
  Dianat, N., Steichen, C., Vallier, L., Weber, A., and Dubart‐Kupperschmitt, A. 2013. Human pluripotent stem cells for modelling human liver diseases and cell therapy. Curr. Gene Ther. 13:120‐132. doi: 10.2174/1566523211313020006.
  Dimos, J.T., Rodolfa, K.T., Niakan, K.K., Weisenthal, L.M., Mitsumoto, H., Chung, W., Croft, G.F., Saphier, G., Leibel, R., Goland, R., Wichterle, H., Henderson, C.E., and Eggan, K. 2008. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321:1218‐1221. doi: 10.1126/science.1158799.
  Ding, Q., Strong, A., Patel, K.M., Ng, S.L., Gosis, B.S., Regan, S.N., Cowan, C.A., Rader, D.J., and Musunuru, K. 2014. Permanent alteration of PCSK9 with in vivo CRISPR‐Cas9 genome editing. Circ. Res. 115:488‐492. doi: 10.1161/CIRCRESAHA.115.304351.
  Duan, Y., Ma, X., Zou, W., Wang, C., Bahbahan, I.S., Ahuja, T.P., Tolstikov, V., and Zern, M.A. 2010. Differentiation and characterization of metabolically functioning hepatocytes from human embryonic stem cells. Stem Cells 28:674‐686. doi: 10.1002/stem.315.
  Ebert, A.D., Yu, J., Rose, F.F., Jr., Mattis, V.B., Lorson, C.L., Thomson, J.A., and Svendsen, C.N. 2009. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457:277‐280. doi: 10.1038/nature07677.
  Egashira, T., Yuasa, S., and Fukuda, K. 2013. Novel insights into disease modeling using induced pluripotent stem cells. Biol. Pharm. Bull. 36:182‐188. doi: 10.1248/bpb.b12‐00960.
  Eggenschwiler, R., Loya, K., Wu, G., Sharma, A.D., Sgodda, M., Zychlinski, D., Herr, C., Steinemann, D., Teckman, J., Bals, R., Ott, M., Schambach, A., Scholer, H.R., and Cantz, T. 2013. Sustained knockdown of a disease‐causing gene in patient‐specific induced pluripotent stem cells using lentiviral vector‐based gene therapy. Stem Cells Transl. Med. 2:641‐654. doi: 10.5966/sctm.2013‐0017.
  Ekins, S., Bradford, J., Dole, K., Spektor, A., Gregory, K., Blondeau, D., Hohman, M., and Bunin, B.A. 2010. A collaborative database and computational models for tuberculosis drug discovery. Mol. Biosyst. 6:840‐851. doi: 10.1039/b917766c.
  Engle, S.J. and Puppala, D. 2013. Integrating human pluripotent stem cells into drug development. Cell Stem Cell 12:669‐677. doi: 10.1016/j.stem.2013.05.011.
  Farzaneh, Z., Pakzad, M., Vosough, M., Pournasr, B., and Baharvand, H. 2014. Differentiation of human embryonic stem cells to hepatocyte‐like cells on a new developed xeno‐free extracellular matrix. Histochem. Cell Biol. 142:217‐226. doi: 10.1007/s00418‐014‐1183‐4.
  Feng, B., Jiang, J., Kraus, P., Ng, J.H., Heng, J.C., Chan, Y.S., Yaw, L.P., Zhang, W., Loh, Y.H., Han, J., Vega, V.B., Cacheux‐Rataboul, V., Lim, B., Lufkin, T., and Ng, H.H. 2009. Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nat. Cell Biol. 11:197‐203. doi: 10.1038/ncb1827.
  Ghodsizadeh, A., Taei, A., Totonchi, M., Seifinejad, A., Gourabi, H., Pournasr, B., Aghdami, N., Malekzadeh, R., Almadani, N., Salekdeh, G.H., and Baharvand, H. 2010. Generation of liver disease‐specific induced pluripotent stem cells along with efficient differentiation to functional hepatocyte‐like cells. Stem Cell Rev. 6:622‐632. doi: 10.1007/s12015‐010‐9189‐3.
  Gieseck, R.L., 3rd, Hannan, N.R., Bort, R., Hanley, N.A., Drake, R.A., Cameron, G.W., Wynn, T.A., and Vallier, L. 2014. Maturation of induced pluripotent stem cell derived hepatocytes by 3D‐culture. PLoS One 9:e86372. doi: 10.1371/journal.pone.0086372.
  Gramignoli, R., Tahan, V., Dorko, K., Skvorak, K.J., Hansel, M.C., Zhao, W., Venkataramanan, R., Ellis, E.C., Jorns, C., Ericzon, B.G., Rosenborg, S., Kuiper, R., Soltys, K.A., Mazariegos, G.V., Fox, I.J., Wilson, E.M., Grompe, M., and Strom, S.C. 2013. New potential cell source for hepatocyte transplantation: Discarded livers from metabolic disease liver transplants. Stem Cell Res. 11:563‐573. doi: 10.1016/j.scr.2013.03.002.
  Grieshammer, U. and Shepard, K.A. 2014. Proceedings: Consideration of genetics in the design of induced pluripotent stem cell‐based models of complex disease. Stem Cells Transl. Med. 3:1253‐1258. doi: 10.5966/sctm.2014‐0191.
  Guha, P., Morgan, J.W., Mostoslavsky, G., Rodrigues, N.P., and Boyd, A.S. 2013. Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells. Cell Stem Cell 12:407‐412. doi: 10.1016/j.stem.2013.01.006.
  Hansel, M.C., Gramignoli, R., Blake, W., Davila, J., Skvorak, K., Dorko, K., Tahan, V., Lee, B.R., Tafaleng, E., Guzman‐Lepe, J., Soto‐Gutierrez, A., Fox, I.J., and Strom, S.C. 2014. Increased reprogramming of human fetal hepatocytes compared with adult hepatocytes in feeder‐free conditions. Cell Transplant 23:27‐38. doi: 10.3727/096368912X662453.
  Hay, D.C., Zhao, D., Fletcher, J., Hewitt, Z.A., McLean, D., Urruticoechea‐Uriguen, A., Black, J.R., Elcombe, C., Ross, J.A., Wolf, R., and Cui, W. 2008b. Efficient differentiation of hepatocytes from human embryonic stem cells exhibiting markers recapitulating liver development in vivo. Stem Cells 26:894‐902. doi: 10.1634/stemcells.2007‐0718.
  Hay, D.C., Fletcher, J., Payne, C., Terrace, J.D., Gallagher, R.C., Snoeys, J., Black, J.R., Wojtacha, D., Samuel, K., Hannoun, Z., Pryde, A., Filippi, C., Currie, I.S., Forbes, S.J., Ross, J.A., Newsome, P.N., and Iredale, J.P. 2008a. Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling. Proc. Natl. Acad. Sci. U. S. A. 105:12301‐12306. doi: 10.1073/pnas.0806522105.
  Hockemeyer, D., Soldner, F., Cook, E.G., Gao, Q., Mitalipova, M., and Jaenisch, R. 2008. A drug‐inducible system for direct reprogramming of human somatic cells to pluripotency. Cell Stem Cell 3:346‐353. doi: 10.1016/j.stem.2008.08.014.
  Huang, H.P., Chen, P.H., Yu, C.Y., Chuang, C.Y., Stone, L., Hsiao, W.C., Li, C.L., Tsai, S.C., Chen, K.Y., Chen, H.F., Ho, H.N., and Kuo, H.C. 2011. Epithelial cell adhesion molecule (EpCAM) complex proteins promote transcription factor‐mediated pluripotency reprogramming. J. Biol. Chem. 286:33520‐33532. doi: 10.1074/jbc.M111.256164.
  Huangfu, D., Osafune, K., Maehr, R., Guo, W., Eijkelenboom, A., Chen, S., Muhlestein, W., and Melton, D.A. 2008. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat. Biotechnol. 26:1269‐1275. doi: 10.1038/nbt.1502.
  Hussain, K., Challis, B., Rocha, N., Payne, F., Minic, M., Thompson, A., Daly, A., Scott, C., Harris, J., Smillie, B.J., Savage, D.B., Ramaswami, U., De Lonlay, P., O'Rahilly, S., Barroso, I., and Semple, R.K. 2011. An activating mutation of AKT2 and human hypoglycemia. Science 334:474. doi: 10.1126/science.1210878.
  Inoue, H. and Yamanaka, S. 2011. The use of induced pluripotent stem cells in drug development. Clin. Pharmacol. Ther. 89:655‐661. doi: 10.1038/clpt.2011.38.
  Inoue, H., Nagata, N., Kurokawa, H., and Yamanaka, S. 2014. iPS cells: A game changer for future medicine. EMBO J. 33:409‐417. doi: 10.1002/embj.201387098.
  Irudayam, J.I., Contreras, D., Sivasubramaniam, S., and Arumugaswami, V. 2014. Modeling Liver Diseases Using Induced Pluripotent Stem Cell (iPSC)‐Derived Hepatocytes. J. Stem Cell Res. Ther. 4. doi: 10.4172/2157‐7633.1000218.
  Isasi, R. and Knoppers, B.M. 2011. From banking to international governance: Fostering innovation in stem cell research. Stem Cells Int. 2011:498132. doi: 10.4061/2011/498132.
  Jia, F., Wilson, K.D., Sun, N., Gupta, D.M., Huang, M., Li, Z., Panetta, N.J., Chen, Z.Y., Robbins, R.C., Kay, M.A., Longaker, M.T., and Wu, J.C. 2010. A nonviral minicircle vector for deriving human iPS cells. Nat. Methods 7:197‐199. doi: 10.1038/nmeth.1426.
  Kajiwara, M., Aoi, T., Okita, K., Takahashi, R., Inoue, H., Takayama, N., Endo, H., Eto, K., Toguchida, J., Uemoto, S., and Yamanaka, S. 2012. Donor‐dependent variations in hepatic differentiation from human‐induced pluripotent stem cells. Proc. Natl. Acad. Sci. U. S. A. 109:12538‐12543. doi: 10.1073/pnas.1209979109.
  Kazuki, Y., Hiratsuka, M., Takiguchi, M., Osaki, M., Kajitani, N., Hoshiya, H., Hiramatsu, K., Yoshino, T., Kazuki, K., Ishihara, C., Takehara, S., Higaki, K., Nakagawa, M., Takahashi, K., Yamanaka, S., and Oshimura, M. 2010. Complete genetic correction of ips cells from Duchenne muscular dystrophy. Mol. Ther. 18:386‐393. doi: 10.1038/mt.2009.274.
  Kim, D., Kim, C.H., Moon, J.I., Chung, Y.G., Chang, M.Y., Han, B.S., Ko, S., Yang, E., Cha, K.Y., Lanza, R., and Kim, K.S. 2009. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4:472‐476. doi: 10.1016/j.stem.2009.05.005.
  Kim, K., Doi, A., Wen, B., Ng, K., Zhao, R., Cahan, P., Kim, J., Aryee, M.J., Ji, H., Ehrlich, L.I., Yabuuchi, A., Takeuchi, A., Cunniff, K.C., Hongguang, H., McKinney‐Freeman, S., Naveiras, O., Yoon, T.J., Irizarry, R.A., Jung, N., Seita, J., Hanna, J., Murakami, P., Jaenisch, R., Weissleder, R., Orkin, S.H., Weissman, I.L., Feinberg, A.P., and Daley, G.Q. 2010. Epigenetic memory in induced pluripotent stem cells. Nature 467:285‐292. doi: 10.1038/nature09342.
  Kiskinis, E. and Eggan, K. 2010. Progress toward the clinical application of patient‐specific pluripotent stem cells. J. Clin. Invest. 120:51‐59. doi: 10.1172/JCI40553.
  Kleger, A., Mahaddalkar, P.U., Katz, S.F., Lechel, A., Joo, J.Y., Loya, K., Lin, Q., Hartmann, D., Liebau, S., Kraus, J.M., Cantz, T., Kestler, H.A., Zaehres, H., Scholer, H., and Rudolph, K.L. 2012. Increased reprogramming capacity of mouse liver progenitor cells, compared with differentiated liver cells, requires the BAF complex. Gastroenterology.
  Kolaja, K. 2014. Stem cells and stem cell‐derived tissues and their use in safety assessment. J. Biol. Chem. 289:4555‐4561. doi: 10.1074/jbc.R113.481028.
  Lee, S.B., Seo, D., Choi, D., Park, K.Y., Holczbauer, A., Marquardt, J.U., Conner, E.A., Factor, V.M., and Thorgeirsson, S.S. 2012. Contribution of Hepatic Lineage Stage‐Specific Donor Memory to the Differential Potential of Induced Mouse Pluripotent Stem Cells (IPSC). Stem Cells.
  Lee, G., Papapetrou, E.P., Kim, H., Chambers, S.M., Tomishima, M.J., Fasano, C.A., Ganat, Y.M., Menon, J., Shimizu, F., Viale, A., Tabar, V., Sadelain, M., and Studer, L. 2009. Modelling pathogenesis and treatment of familial dysautonomia using patient‐specific iPSCs. Nature 461:402‐406. doi: 10.1038/nature08320.
  Lee, J., Kim, Y., Yi, H., Diecke, S., Kim, J., Jung, H., Rim, Y.A., Jung, S.M., Kim, M., Kim, Y.G., Park, S.H., Kim, H.Y., and Ju, J.H. 2014. Generation of disease‐specific induced pluripotent stem cells from patients with rheumatoid arthritis and osteoarthritis. Arthritis. Res. Ther. 16:R41. doi: 10.1186/ar4470.
  Li, M., Suzuki, K., Kim, N.Y., Liu, G.H., and Izpisua Belmonte, J.C. 2014. A cut above the rest: Targeted genome editing technologies in human pluripotent stem cells. J. Biol. Chem. 289:4594‐4599. doi: 10.1074/jbc.R113.488247.
  Li, Y., Zhao, H., Lan, F., Lee, A., Chen, L., Lin, C., Yao, Y., and Li, L. 2010. Generation of human‐induced pluripotent stem cells from gut mesentery‐derived cells by ectopic expression of OCT4/SOX2/NANOG. Cell Reprogram 12:237‐247. doi: 10.1089/cell.2009.0103.
  Liao, J., Wu, Z., Wang, Y., Cheng, L., Cui, C., Gao, Y., Chen, T., Rao, L., Chen, S., Jia, N., Dai, H., Xin, S., Kang, J., Pei, G., and Xiao, L. 2008. Enhanced efficiency of generating induced pluripotent stem (iPS) cells from human somatic cells by a combination of six transcription factors. Cell Res. 18:600‐603. doi: 10.1038/cr.2008.51.
  Lin, T., Ambasudhan, R., Yuan, X., Li, W., Hilcove, S., Abujarour, R., Lin, X., Hahm, H.S., Hao, E., Hayek, A., and Ding, S. 2009. A chemical platform for improved induction of human iPSCs. Nat. Methods 6:805‐808. doi: 10.1038/nmeth.1393.
  Liu, H., Ye, Z., Kim, Y., Sharkis, S., and Jang, Y.Y. 2010. Generation of endoderm‐derived human induced pluripotent stem cells from primary hepatocytes. Hepatology 51:1810‐1819. doi: 10.1002/hep.23626.
  Liu, H., Kim, Y., Sharkis, S., Marchionni, L., and Jang, Y.Y. 2011. In vivo liver regeneration potential of human induced pluripotent stem cells from diverse origins. Sci. Transl. Med. 3:82ra39. doi: 10.1126/scitranslmed.3002376.
  Lowenthal, J., Lipnick, S., Rao, M., and Hull, S.C. 2012. Specimen collection for induced pluripotent stem cell research: Harmonizing the approach to informed consent. Stem Cells Transl. Med. 1:409‐421. doi: 10.5966/sctm.2012‐0029.
  Luong, M.X., Auerbach, J., Crook, J.M., Daheron, L., Hei, D., Lomax, G., Loring, J.F., Ludwig, T., Schlaeger, T.M., Smith, K.P., Stacey, G., Xu, R.H., and Zeng, F. 2011. A call for standardized naming and reporting of human ESC and iPSC lines. Cell Stem Cell 8:357‐359. doi: 10.1016/j.stem.2011.03.002.
  Mali, P., Ye, Z., Hommond, H.H., Yu, X., Lin, J., Chen, G., Zou, J., and Cheng, L. 2008. Improved efficiency and pace of generating induced pluripotent stem cells from human adult and fetal fibroblasts. Stem Cells 26:1998‐2005. doi: 10.1634/stemcells.2008‐0346.
  Martell, K., Trounson, A., and Baum, E. 2010. Stem cell therapies in clinical trials: Workshop on best practices and the need for harmonization. Cell Stem Cell 7:451‐454. doi: 10.1016/j.stem.2010.09.004.
  McLean, A.B., D'Amour, K.A., Jones, K.L., Krishnamoorthy, M., Kulik, M.J., Reynolds, D.M., Sheppard, A.M., Liu, H., Xu, Y., Baetge, E.E., and Dalton, S. 2007. Activin a efficiently specifies definitive endoderm from human embryonic stem cells only when phosphatidylinositol 3‐kinase signaling is suppressed. Stem Cells 25:29‐38. doi: 10.1634/stemcells.2006‐0219.
  Medine, C.N., Lucendo‐Villarin, B., Zhou, W., West, C.C., and Hay, D.C. 2011. Robust generation of hepatocyte‐like cells from human embryonic stem cell populations. J. Vis. Exp. e2969.
  Medine, C.N., Lucendo‐Villarin, B., Storck, C., Wang, F., Szkolnicka, D., Khan, F., Pernagallo, S., Black, J.R., Marriage, H.M., Ross, J.A., Bradley, M., Iredale, J.P., Flint, O., and Hay, D.C. 2013. Developing high‐fidelity hepatotoxicity models from pluripotent stem cells. Stem Cells Transl. Med. 2:505‐509. doi: 10.5966/sctm.2012‐0138.
  Meng, X.L., Shen, J.S., Kawagoe, S., Ohashi, T., Brady, R.O., and Eto, Y. 2010. Induced pluripotent stem cells derived from mouse models of lysosomal storage disorders. Proc. Natl. Acad. Sci. U. S. A. 107:7886‐7891. doi: 10.1073/pnas.1002758107.
  Merkle, F.T. and Eggan, K. 2013. Modeling human disease with pluripotent stem cells: From genome association to function. Cell Stem Cell 12:656‐668. doi: 10.1016/j.stem.2013.05.016.
  Montserrat, N., Garreta, E., Gonzalez, F., Gutierrez, J., Eguizabal, C., Ramos, V., Borros, S., and Izpisua Belmonte, J.C. 2011. Simple generation of human induced pluripotent stem cells using poly‐beta‐amino esters as the non‐viral gene delivery system. J. Biol. Chem. 286:12417‐12428. doi: 10.1074/jbc.M110.168013.
  Montserrat, N., de Onate, L., Garreta, E., Gonzalez, F., Adamo, A., Eguizabal, C., Hafner, S., Vassena, R., and Izpisua Belmonte, J.C. 2012. Generation of feeder‐free pig induced pluripotent stem cells without Pou5f1. Cell Transplant. 21:815‐825. doi: 10.3727/096368911X601019.
  Moriya, K., Yoshikawa, M., Ouji, Y., Saito, K., Nishiofuku, M., Matsuda, R., Ishizaka, S., and Fukui, H. 2008. Embryonic stem cells reduce liver fibrosis in CCl4‐treated mice. Int. J. Exp. Pathol. 89:401‐409. doi: 10.1111/j.1365‐2613.2008.00607.x.
  Morrison, G.M., Oikonomopoulou, I., Migueles, R.P., Soneji, S., Livigni, A., Enver, T., and Brickman, J.M. 2008. Anterior definitive endoderm from ESCs reveals a role for FGF signaling. Cell Stem Cell 3:402‐415. doi: 10.1016/j.stem.2008.07.021.
  Nagata, S., Toyoda, M., Yamaguchi, S., Hirano, K., Makino, H., Nishino, K., Miyagawa, Y., Okita, H., Kiyokawa, N., Nakagawa, M., Yamanaka, S., Akutsu, H., Umezawa, A., and Tada, T. 2009. Efficient reprogramming of human and mouse primary extra‐embryonic cells to pluripotent stem cells. Genes Cells 14:1395‐1404. doi: 10.1111/j.1365‐2443.2009.01356.x.
  Nori, S., Okada, Y., Yasuda, A., Tsuji, O., Takahashi, Y., Kobayashi, Y., Fujiyoshi, K., Koike, M., Uchiyama, Y., Ikeda, E., Toyama, Y., Yamanaka, S., Nakamura, M., and Okano, H. 2011. Grafted human‐induced pluripotent stem‐cell‐derived neurospheres promote motor functional recovery after spinal cord injury in mice. Proc. Natl. Acad. Sci. U. S. A. 108:16825‐16830. doi: 10.1073/pnas.1108077108.
  Ogawa, S., Surapisitchat, J., Virtanen, C., Ogawa, M., Niapour, M., Sugamori, K.S., Wang, S., Tamblyn, L., Guillemette, C., Hoffmann, E., Zhao, B., Strom, S., Laposa, R.R., Tyndale, R.F., Grant, D.M., and Keller, G. 2013. Three‐dimensional culture and cAMP signaling promote the maturation of human pluripotent stem cell‐derived hepatocytes. Development 140:3285‐3296. doi: 10.1242/dev.090266.
  Park, I.H., Zhao, R., West, J.A., Yabuuchi, A., Huo, H., Ince, T.A., Lerou, P.H., Lensch, M.W., and Daley, G.Q. 2008b. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141‐146. doi: 10.1038/nature06534.
  Park, I.H., Arora, N., Huo, H., Maherali, N., Ahfeldt, T., Shimamura, A., Lensch, M.W., Cowan, C., Hochedlinger, K., and Daley, G.Q. 2008a. Disease‐specific induced pluripotent stem cells. Cell 134:877‐886. doi: 10.1016/j.cell.2008.07.041.
  Pasca, S.P., Portmann, T., Voineagu, I., Yazawa, M., Shcheglovitov, A., Pasca, A.M., Cord, B., Palmer, T.D., Chikahisa, S., Nishino, S., Bernstein, J.A., Hallmayer, J., Geschwind, D.H., and Dolmetsch, R.E. 2011. Using iPSC‐derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat. Med. 17:1657‐1662. doi: 10.1038/nm.2576.
  Peterson, S.E. and Loring, J.F. 2014. Genomic instability in pluripotent stem cells: Implications for clinical applications. J. Biol. Chem. 289:4578‐4584. doi: 10.1074/jbc.R113.516419.
  Polo, J.M., Liu, S., Figueroa, M.E., Kulalert, W., Eminli, S., Tan, K.Y., Apostolou, E., Stadtfeld, M., Li, Y., Shioda, T., Natesan, S., Wagers, A.J., Melnick, A., Evans, T., and Hochedlinger, K. 2010. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat. Biotechnol. 28:848‐855. doi: 10.1038/nbt.1667.
  Ran, F.A., Hsu, P.D., Wright, J., Agarwala, V., Scott, D.A., and Zhang, F. 2013. Genome engineering using the CRISPR‐Cas9 system. Nat. Protoc. 8:2281‐2308. doi: 10.1038/nprot.2013.143.
  Rashid, S.T., Corbineau, S., Hannan, N., Marciniak, S.J., Miranda, E., Alexander, G., Huang‐Doran, I., Griffin, J., Ahrlund‐Richter, L., Skepper, J., Semple, R., Weber, A., Lomas, D.A., and Vallier, L. 2010. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J. Clin. Invest. 120:3127‐3136. doi: 10.1172/JCI43122.
  Raya, A., Rodriguez‐Piza, I., Guenechea, G., Vassena, R., Navarro, S., Barrero, M.J., Consiglio, A., Castella, M., Rio, P., Sleep, E., Gonzalez, F., Tiscornia, G., Garreta, E., Aasen, T., Veiga, A., Verma, I.M., Surralles, J., Bueren, J., and Izpisua Belmonte, J.C. 2009. Disease‐corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460:53‐59. doi: 10.1038/nature08129.
  Rowntree, R.K. and McNeish, J.D. 2010. Induced pluripotent stem cells: Opportunities as research and development tools in 21st century drug discovery. Regen. Med. 5:557‐568. doi: 10.2217/rme.10.36.
  Sanchez‐Danes, A., Richaud‐Patin, Y., Carballo‐Carbajal, I., Jimenez‐Delgado, S., Caig, C., Mora, S., Di Guglielmo, C., Ezquerra, M., Patel, B., Giralt, A., Canals, J.M., Memo, M., Alberch, J., Lopez‐Barneo, J., Vila, M., Cuervo, A.M., Tolosa, E., Consiglio, A., and Raya, A. 2012. Disease‐specific phenotypes in dopamine neurons from human iPS‐based models of genetic and sporadic Parkinson's disease. EMBO Mol. Med. 4:380‐395. doi: 10.1002/emmm.201200215.
  Sancho‐Bru, P., Roelandt, P., Narain, N., Pauwelyn, K., Notelaers, T., Shimizu, T., Ott, M., and Verfaillie, C. 2011. Directed differentiation of murine‐induced pluripotent stem cells to functional hepatocyte‐like cells. J. Hepatol. 54:98‐107. doi: 10.1016/j.jhep.2010.06.014.
  Schwartz, R.E., Trehan, K., Andrus, L., Sheahan, T.P., Ploss, A., Duncan, S.A., Rice, C.M., and Bhatia, S.N. 2012. Modeling hepatitis C virus infection using human induced pluripotent stem cells. Proc. Natl. Acad. Sci. U. S. A. 109:2544‐2548. doi: 10.1073/pnas.1121400109.
  Sebastiano, V., Maeder, M.L., Angstman, J.F., Haddad, B., Khayter, C., Yeo, D.T., Goodwin, M.J., Hawkins, J.S., Ramirez, C.L., Batista, L.F., Artandi, S.E., Wernig, M., and Joung, J.K. 2011. In situ genetic correction of the sickle cell anemia mutation in human induced pluripotent stem cells using engineered zinc finger nucleases. Stem Cells 29:1717‐1726. doi: 10.1002/stem.718.
  Seguin, C.A., Draper, J.S., Nagy, A., and Rossant, J. 2008. Establishment of endoderm progenitors by SOX transcription factor expression in human embryonic stem cells. Cell Stem Cell 3:182‐195. doi: 10.1016/j.stem.2008.06.018.
  Seifinejad, A., Tabebordbar, M., Baharvand, H., Boyer, L.A., and Salekdeh, G.H. 2010. Progress and promise towards safe induced pluripotent stem cells for therapy. Stem Cell Rev. 6:297‐306. doi: 10.1007/s12015‐010‐9121‐x.
  Sengupta, S., Johnson, B.P., Swanson, S.A., Stewart, R., Bradfield, C.A., and Thomson, J.A. 2014. Aggregate culture of human embryonic stem cell‐derived hepatocytes in suspension are an improved in vitro model for drug metabolism and toxicity testing. Toxicol. Sci. 140:236‐245. doi: 10.1093/toxsci/kfu069.
  Shan, J., Schwartz, R.E., Ross, N.T., Logan, D.J., Thomas, D., Duncan, S.A., North, T.E., Goessling, W., Carpenter, A.E., and Bhatia, S.N. 2013. Identification of small molecules for human hepatocyte expansion and iPS differentiation. Nat. Chem. Biol. 9:514‐520. doi: 10.1038/nchembio.1270.
  Sharma, N.S., Wallenstein, E.J., Novik, E., Maguire, T., Schloss, R., and Yarmush, M.L. 2009. Enrichment of hepatocyte‐like cells with upregulated metabolic and differentiated function derived from embryonic stem cells using S‐NitrosoAcetylPenicillamine. Tissue Eng. Part C Methods 15:297‐306. doi: 10.1089/ten.tec.2008.0303.
  Si‐Tayeb, K., Noto, F.K., Sepac, A., Sedlic, F., Bosnjak, Z.J., Lough, J.W., and Duncan, S.A. 2010b. Generation of human induced pluripotent stem cells by simple transient transfection of plasmid DNA encoding reprogramming factors. BMC Dev. Biol. 10:81. doi: 10.1186/1471‐213X‐10‐81.
  Si‐Tayeb, K., Noto, F.K., Nagaoka, M., Li, J., Battle, M.A., Duris, C., North, P.E., Dalton, S., and Duncan, S.A. 2010a. Highly efficient generation of human hepatocyte‐like cells from induced pluripotent stem cells. Hepatology 51:297‐305. doi: 10.1002/hep.23354.
  Smith, Z.D., Nachman, I., Regev, A., and Meissner, A. 2010. Dynamic single‐cell imaging of direct reprogramming reveals an early specifying event. Nat. Biotechnol. 28:521‐526. doi: 10.1038/nbt.1632.
  Smith, C., Abalde‐Atristain, L., He, C., Brodsky, B.R., Braunstein, E.M., Chaudhari, P., Jang, Y.Y., Cheng, L., and Ye, Z. 2015. Efficient and allele‐specific genome editing of disease loci in human iPSCs. Mol. Ther. 23:570‐577. doi: 10.1038/mt.2014.226.
  Soldner, F. and Jaenisch, R. 2012. Medicine. iPSC disease modeling. Science 338:1155‐1156. doi: 10.1126/science.1227682.
  Soldner, F., Hockemeyer, D., Beard, C., Gao, Q., Bell, G.W., Cook, E.G., Hargus, G., Blak, A., Cooper, O., Mitalipova, M., Isacson, O., and Jaenisch, R. 2009. Parkinson's disease patient‐derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136:964‐977. doi: 10.1016/j.cell.2009.02.013.
  Song, Z., Cai, J., Liu, Y., Zhao, D., Yong, J., Duo, S., Song, X., Guo, Y., Zhao, Y., Qin, H., Yin, X., Wu, C., Che, J., Lu, S., Ding, M., and Deng, H. 2009. Efficient generation of hepatocyte‐like cells from human induced pluripotent stem cells. Cell Res. 19:1233‐1242. doi: 10.1038/cr.2009.107.
  Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G., and Hochedlinger, K. 2008. Induced pluripotent stem cells generated without viral integration. Science 322:945‐949. doi: 10.1126/science.1162494.
  Stadtfeld, M., Apostolou, E., Akutsu, H., Fukuda, A., Follett, P., Natesan, S., Kono, T., Shioda, T., and Hochedlinger, K. 2010. Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature 465:175‐181. doi: 10.1038/nature09017.
  Strom, S.C., Davila, J., and Grompe, M. 2010. Chimeric mice with humanized liver: Tools for the study of drug metabolism, excretion, and toxicity. Methods Mol. Biol. 640:491‐509. doi: 10.1007/978‐1‐60761‐688‐7_27.
  Szkolnicka, D., Farnworth, S.L., Lucendo‐Villarin, B., and Hay, D.C. 2014. Deriving functional hepatocytes from pluripotent stem cells. Curr. Protoc. Stem Cell Biol. 30: 1G.5.1‐1G.5.12. doi: 10.1002/9780470151808.sc01g05s30.
  Tahamtani, Y., Azarnia, M., Farrokhi, A., Moradmand, A., Mirshahvaladi, S., Aghdami, N., and Baharvand, H. 2014. Stauprimide priming of human embryonic stem cells toward definitive endoderm. Cell J. 16:63‐72.
  Takahashi, K. and Yamanaka, S. 2006. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663‐676. doi: 10.1016/j.cell.2006.07.024.
  Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. 2007. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861‐872. doi: 10.1016/j.cell.2007.11.019.
  Takayama, K., Inamura, M., Kawabata, K., Sugawara, M., Kikuchi, K., Higuchi, M., Nagamoto, Y., Watanabe, H., Tashiro, K., Sakurai, F., Hayakawa, T., Furue, M.K., and Mizuguchi, H. 2012. Generation of metabolically functioning hepatocytes from human pluripotent stem cells by FOXA2 and HNF1alpha transduction. J. Hepatol. 57:628‐636. doi: 10.1016/j.jhep.2012.04.038.
  Tanaka, T., Tohyama, S., Murata, M., Nomura, F., Kaneko, T., Chen, H., Hattori, F., Egashira, T., Seki, T., Ohno, Y., Koshimizu, U., Yuasa, S., Ogawa, S., Yamanaka, S., Yasuda, K., and Fukuda, K. 2009. In vitro pharmacologic testing using human induced pluripotent stem cell‐derived cardiomyocytes. Biochem. Biophys. Res. Commun. 385:497‐502. doi: 10.1016/j.bbrc.2009.05.073.
  Tang, C., Lee, A.S., Volkmer, J.P., Sahoo, D., Nag, D., Mosley, A.R., Inlay, M.A., Ardehali, R., Chavez, S.L., Pera, R.R., Behr, B., Wu, J.C., Weissman, I.L., and Drukker, M. 2011. An antibody against SSEA‐5 glycan on human pluripotent stem cells enables removal of teratoma‐forming cells. Nat. Biotechnol. 29:829‐834. doi: 10.1038/nbt.1947.
  Tateishi, K., He, J., Taranova, O., Liang, G., D'Alessio, A.C., and Zhang, Y. 2008. Generation of insulin‐secreting islet‐like clusters from human skin fibroblasts. J. Biol. Chem. 283:31601‐31607. doi: 10.1074/jbc.M806597200.
  Teo, A.K., Ali, Y., Wong, K.Y., Chipperfield, H., Sadasivam, A., Poobalan, Y., Tan, E.K., Wang, S.T., Abraham, S., Tsuneyoshi, N., Stanton, L.W., and Dunn, N.R. 2012. Activin and BMP4 synergistically promote formation of definitive endoderm in human embryonic stem cells. Stem Cells 30:631‐642. doi: 10.1002/stem.1022.
  Thompson, H.L. and Manilay, J.O. 2011. Embryonic stem cell‐derived hematopoietic stem cells: Challenges in development, differentiation, and immunogenicity. Curr. Top. Med. Chem. 11:1621‐1637. doi: 10.2174/156802611796117702.
  Thomson, J.A., Itskovitz‐Eldor, J., Shapiro, S.S., Waknitz, M.A., Swiergiel, J.J., Marshall, V.S., and Jones, J.M. 1998. Embryonic stem cell lines derived from human blastocysts. Science 282:1145‐1147. doi: 10.1126/science.282.5391.1145.
  Touboul, T., Hannan, N.R., Corbineau, S., Martinez, A., Martinet, C., Branchereau, S., Mainot, S., Strick‐Marchand, H., Pedersen, R., Di Santo, J., Weber, A., and Vallier, L. 2010. Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions that recapitulate liver development. Hepatology 51:1754‐1765. doi: 10.1002/hep.23506.
  Tuleuova, N., Lee, J.Y., Lee, J., Ramanculov, E., Zern, M.A., and Revzin, A. 2010. Using growth factor arrays and micropatterned co‐cultures to induce hepatic differentiation of embryonic stem cells. Biomaterials 31:9221‐9231. doi: 10.1016/j.biomaterials.2010.08.050.
  Turner, M., Leslie, S., Martin, N.G., Peschanski, M., Rao, M., Taylor, C.J., Trounson, A., Turner, D., Yamanaka, S., and Wilmut, I. 2013. Toward the development of a global induced pluripotent stem cell library. Cell Stem Cell 13:382‐384. doi: 10.1016/j.stem.2013.08.003.
  Vosough, M., Omidinia, E., Kadivar, M., Shokrgozar, M.A., Pournasr, B., Aghdami, N., and Baharvand, H. 2013. Generation of functional hepatocyte‐like cells from human pluripotent stem cells in a scalable suspension culture. Stem Cells Dev 22:2693‐2705. doi: 10.1089/scd.2013.0088.
  Wang, W., Yang, J., Liu, H., Lu, D., Chen, X., Zenonos, Z., Campos, L.S., Rad, R., Guo, G., Zhang, S., Bradley, A., and Liu, P. 2011. Rapid and efficient reprogramming of somatic cells to induced pluripotent stem cells by retinoic acid receptor gamma and liver receptor homolog 1. Proc. Natl. Acad. Sci. U. S. A. 108:18283‐18288. doi: 10.1073/pnas.1100893108.
  Warren, L., Manos, P.D., Ahfeldt, T., Loh, Y.H., Li, H., Lau, F., Ebina, W., Mandal, P.K., Smith, Z.D., Meissner, A., Daley, G.Q., Brack, A.S., Collins, J.J., Cowan, C., Schlaeger, T.M., and Rossi, D.J. 2010. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7:618‐630. doi: 10.1016/j.stem.2010.08.012.
  Wilmut, I., Schnieke, A.E., McWhir, J., Kind, A.J., and Campbell, K.H. 1997. Viable offspring derived from fetal and adult mammalian cells. Nature 385:810‐813. doi: 10.1038/385810a0.
  Xue, W., Chen, S., Yin, H., Tammela, T., Papagiannakopoulos, T., Joshi, N.S., Cai, W., Yang, G., Bronson, R., Crowley, D.G., Zhang, F., Anderson, D.G., Sharp, P.A., and Jacks, T. 2014. CRISPR‐mediated direct mutation of cancer genes in the mouse liver. Nature 514:380‐384. doi: 10.1038/nature13589.
  Yakubov, E., Rechavi, G., Rozenblatt, S., and Givol, D. 2010. Reprogramming of human fibroblasts to pluripotent stem cells using mRNA of four transcription factors. Biochem. Biophys. Res. Commun. 394:189‐193. doi: 10.1016/j.bbrc.2010.02.150.
  Ye, L., Chang, J.C., Lin, C., Qi, Z., Yu, J., and Kan, Y.W. 2010. Generation of induced pluripotent stem cells using site‐specific integration with phage integrase. Proc. Natl. Acad. Sci. U. S. A. 107:19467‐19472. doi: 10.1073/pnas.1012677107.
  Yin, H., Xue, W., Chen, S., Bogorad, R.L., Benedetti, E., Grompe, M., Koteliansky, V., Sharp, P.A., Jacks, T., and Anderson, D.G. 2014. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat. Biotechnol. 32:551‐553. doi: 10.1038/nbt.2884.
  Yokoo, N., Baba, S., Kaichi, S., Niwa, A., Mima, T., Doi, H., Yamanaka, S., Nakahata, T., and Heike, T. 2009. The effects of cardioactive drugs on cardiomyocytes derived from human induced pluripotent stem cells. Biochem. Biophys. Res. Commun. 387:482‐488. doi: 10.1016/j.bbrc.2009.07.052.
  Yoshida, Y., Takahashi, K., Okita, K., Ichisaka, T., and Yamanaka, S. 2009. Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell 5:237‐241. doi: 10.1016/j.stem.2009.08.001.
  Young, M.A., Larson, D.E., Sun, C.W., George, D.R., Ding, L., Miller, C.A., Lin, L., Pawlik, K.M., Chen, K., Fan, X., Schmidt, H., Kalicki‐Veizer, J., Cook, L.L., Swift, G.W., Demeter, R.T., Wendl, M.C., Sands, M.S., Mardis, E.R., Wilson, R.K., Townes, T.M., and Ley, T.J. 2012. Background mutations in parental cells account for most of the genetic heterogeneity of induced pluripotent stem cells. Cell Stem Cell 10:570‐582. doi: 10.1016/j.stem.2012.03.002.
  Yu, J., Hu, K., Smuga‐Otto, K., Tian, S., Stewart, R., Slukvin, II, and Thomson, J.A. 2009. Human induced pluripotent stem cells free of vector and transgene sequences. Science 324:797‐801. doi: 10.1126/science.1172482.
  Yu, J., Vodyanik, M.A., Smuga‐Otto, K., Antosiewicz‐Bourget, J., Frane, J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., Slukvin, II, and Thomson, J.A. 2007. Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917‐1920. doi: 10.1126/science.1151526.
  Yusa, K., Rashid, S.T., Strick‐Marchand, H., Varela, I., Liu, P.Q., Paschon, D.E., Miranda, E., Ordonez, A., Hannan, N.R., Rouhani, F.J., Darche, S., Alexander, G., Marciniak, S.J., Fusaki, N., Hasegawa, M., Holmes, M.C., Di Santo, J.P., Lomas, D.A., Bradley, A., and Vallier, L. 2011. Targeted gene correction of alpha1‐antitrypsin deficiency in induced pluripotent stem cells. Nature 478:391‐394. doi: 10.1038/nature10424.
  Zhang, J., Wilson, G.F., Soerens, A.G., Koonce, C.H., Yu, J., Palecek, S.P., Thomson, J.A., and Kamp, T.J. 2009. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ. Res. 104:e30‐41. doi: 10.1161/CIRCRESAHA.108.192237.
  Zhang, S., Chen, S., Li, W., Guo, X., Zhao, P., Xu, J., Chen, Y., Pan, Q., Liu, X., Zychlinski, D., Lu, H., Tortorella, M.D., Schambach, A., Wang, Y., Pei, D., and Esteban, M.A. 2011. 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. 20:3176‐3187. doi: 10.1093/hmg/ddr223.
  Zhao, T., Zhang, Z.N., Rong, Z., and Xu, Y. 2011. Immunogenicity of induced pluripotent stem cells. Nature 474:212‐215. doi: 10.1038/nature10135.
  Zhao, H.X., Li, Y., Jin, H.F., Xie, L., Liu, C., Jiang, F., Luo, Y.N., Yin, G.W., Wang, J., Li, L.S., Yao, Y.Q., and Wang, X.H. 2010. Rapid and efficient reprogramming of human amnion‐derived cells into pluripotency by three factors OCT4/SOX2/NANOG. Differentiation 80:123‐129. doi: 10.1016/j.diff.2010.03.002.
  Zhao, Y., Yin, X., Qin, H., Zhu, F., Liu, H., Yang, W., Zhang, Q., Xiang, C., Hou, P., Song, Z., Liu, Y., Yong, J., Zhang, P., Cai, J., Liu, M., Li, H., Li, Y., Qu, X., Cui, K., Zhang, W., Xiang, T., Wu, Y., Liu, C., Yu, C., Yuan, K., Lou, J., Ding, M., and Deng, H. 2008. Two supporting factors greatly improve the efficiency of human iPSC generation. Cell Stem Cell 3:475‐479. doi: 10.1016/j.stem.2008.10.002.
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