Applications of Human Induced Pluripotent Stem Cell Derived Hepatocytes

  • Hua Liu
  • Pooja Chaudhari
  • Su Mi Choi
  • Yoon-Young Jang
Part of the Stem Cells and Cancer Stem Cells book series (STEM, volume 3)


Human induced pluripotent stem cells (iPSCs) are potential sources of hepatocytes for drug development and cell therapy. In vitro differentiation of iPSCs into hepatic cells has been achieved and improved during the last several years. More recently the in vivo functionality of human iPSC-derived hepatic cells at various differentiation stages has also been demonstrated. In this chapter, we describe the recent advance in human iPSC generation and hepatic differentiation technologies, the in vitro and in vivo activities of human iPSC derived hepatocytes, and discuss both basic and clinical applications of these cells including disease modeling, drug toxicity screening, drug discovery, gene therapy and cell replacement therapy.


Pluripotent iPSCs Hepatocytes Liver Disease modeling Cell replacement therapy 


  1. Agarwal S, Holton KL, Lanza R (2008) Efficient differentiation of functional hepatocytes from human embryonic stem cells. Stem Cells 26:1117–1127PubMedCrossRefGoogle Scholar
  2. Anokye-Danso F, Trivedi CM, Juhr D, Gupta M, Cui Z, Tian Y, Zhang Y, Yang W, Gruber PJ, Epstein JA, Morrisey EE (2011) Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 8:376–388PubMedCrossRefGoogle Scholar
  3. Bluteau O, Jeannot E, Bioulac-Sage P, Marqués JM, Blanc JF, Bui H, Beaudoin JC, Franco D, Balabaud C, Laurent-Puig P, Zucman-Rossi J (2002) Bi-allelic inactivation of TCF1 in hepatic adenomas. Nat Genet 32:312–315PubMedCrossRefGoogle Scholar
  4. Choi SM, Liu H, Kim Y, Jang YY (in press) Multistage hepatic differentiation from human induced pluripotent stem cells. Methods Protoc. doi 10.1007/978-1-61779-267-0_28. ISBN: 978–1–61779–266–3Google Scholar
  5. Chun YS, Chaudhari P, Jang YY (2010) Applications of patient-specific induced pluripotent stem cells; focused on disease modeling, drug screening and therapeutic potentials for liver disease. Int J Biol Sci 6:796–805PubMedGoogle Scholar
  6. Ghodsizadeh A, Taei A, Totonchi M, Seifinejad A, Gourabi H, Pournasr B, Aghdami N, Malekzadeh. R, Almadani N, Salekdeh GH, Baharvand H (2010) Generation of liver disease-specific induced pluripotent stem cells along with efficient differentiation to functional hepatocyte-like cells. Stem Cell Rev Rep 6:622–632CrossRefGoogle Scholar
  7. Hanna J, Wernig M, Markoulaki S, Sun CW, Meissner A, Cassady JP, Beard C, Brambrink T, Wu LC, Townes TM, Jaenisch R (2007) Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318:1920–1923PubMedCrossRefGoogle Scholar
  8. Jang YY, Ye Z, Cheng L (2011) Molecular imaging and stem cell research. Mol Imaging 10:111–122PubMedGoogle Scholar
  9. Jia F, Wilson KD, Sun I’J, Gupta DM, Huang M, Li Z, Panetta NJ, Chen ZY, Robbins RC, Kay MA, Longaker MT, Wu JC (2010) A nonviral minicircle vector for deriving human iPS cells. Nat Methods 7:197–199PubMedCrossRefGoogle Scholar
  10. Kim D, Kim CH, Moon JI, Chung YG, Chang MY, Han BS, Ko S, Yang E, Cha KY, Lanza R, Kim KS (2009) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4:472–476PubMedCrossRefGoogle Scholar
  11. Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, Kim J, Aryee MJ, Ji H, Ehrlich LI, Yabuuchi A, Takeuchi A, Cunniff KC, Hongguang H, McKinney-Freeman S, Naveiras O, Yoon TJ, Irizarry RA, Jung N, Seita J, Hanna J, Murakami P, Jaenisch R, Weissleder R, Orkin SH, Weissman IL, Feinberg AP, Daley GQ (2010) Epigenetic memory in induced pluripotent stem cells. Nature 467:280–290CrossRefGoogle Scholar
  12. Laurent-Puig P, Zucman-Rossi J (2006) Genetics of hepatocelluar tumors. Oncogenes 25:3778–3786CrossRefGoogle Scholar
  13. Liu H, Ye Z, Kim Y, Sharkis S, Jang YY (2010) Generation of endoderm-derived human induced pluripotent stem cells from primary hepatocytes. Hepatology 51:1810–1819PubMedCrossRefGoogle Scholar
  14. Liu H, Kim Y, Sharkis S, Marchionni L, Jang YY (2011) In vivo liver regeneration potential of human induced pluripotent stem cells from diverse origins. Sci Transl Med 3:82ra39PubMedCrossRefGoogle Scholar
  15. Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, Goland R, Leibel RL, Melton DA (2009) Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci USA 106:15768–15773PubMedCrossRefGoogle Scholar
  16. Miura K, Okada Y, Aoi T, Okad A, Takahashi K, Okita K, Nakagawa M, Koyanagi M, Tanabe K, Ohnuki M, Ogawa D, Ikeda E, Okano H, Yamanaka S (2009) Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol 27:743–745PubMedCrossRefGoogle Scholar
  17. Miyoshi N, Ishii H, Nagai K, Hoshino H, Mimori K, Tanaka F, Nagan H, Sekimoto M, Doki Y, Mori M (2010) Defined factors induce reprogramming of gastrointestinal cancer cells. Proc Natl Acad Sci USA 107:40–45PubMedCrossRefGoogle Scholar
  18. Montserrat N, Garreta Bahima E, Gonzalez F, Gutiérrez J, Eguizábal C, Ramos V, Borrós S, Izpisua Belmonte JC (2011) Simple generation of human induced pluripotent stem cells using Poly({beta}-Amino Esters) as non-viral gene delivery system. J Biol Chem 286:12417–12428PubMedCrossRefGoogle Scholar
  19. Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, Daley GQ (2008) Disease-specific induced pluripotent stem cells. Cell 134:877–886PubMedCrossRefGoogle Scholar
  20. Polo JM, Liu S, Figueroa ME, Kulalert W, Eminli S, Tan KY, Apostolou E, Stadtfeld M, Li Y, Shioda T, Natesan S, Wagers AJ, Melnick A, Evans T, Hochedlinger K (2010) Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat Biotechnol 28:848–855PubMedCrossRefGoogle Scholar
  21. Rashid ST, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, Huang-Doran I, Griffin J, Ahrlund-Richter L, Skepper J, Semple R, Weber A, Lomas DA, Vallier L (2010) Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest 120:3127–3136PubMedCrossRefGoogle Scholar
  22. Raya A, Rodriguez-Piza I, Guenechea G, Vassena R, Navarro S, Barrero MJ, Consiglio A, Castellà M, Río P, Sleep E, González F, Tiscornia G, Garreta E, Aasen T, Veiga A, Verma IM, Surrallés J, Bueren J, Izpisúa Belmonte JC (2009) Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460:53–59PubMedCrossRefGoogle Scholar
  23. Rubin LL (2008) Stem cells and drug discovery: the beginning of a new era? Cell 132:549–552PubMedCrossRefGoogle Scholar
  24. Si-Tayeb K, Noto FK, Nagaoka M, Li J, Battle MA, Duris C, North PE, alton S, Duncan SA (2010) Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology 51:297–305PubMedCrossRefGoogle Scholar
  25. 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, Deng H (2009) Efficient generation of hepatocyte-like cells from human induced pluripotent stem cells. Cell Res 19:1233–1242PubMedCrossRefGoogle Scholar
  26. Subramanyam D, Lamouille S, Judson RL, Liu JY, Bucay N, Derynck R, Blelloch R (2011) Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nat Biotechnol 29:443–448Google Scholar
  27. Sullivan GJ, Hay DC, Park IH, Fletcher J, Hannoun Z, Payne CM, Dalgetty D, Black JR, Ross JA, Samuel K, Wang G, Daley GQ, Lee J, Church GM, Forbes SJ, Iredale JP, Wilmut I (2010) Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology 51:329–335PubMedCrossRefGoogle Scholar
  28. Takata A, Otsuka M, Kogiso T, Kojima K, Yoshikaw T, Tateishi R, Kato N, Shiina S, Yoshida H, Omata M, Koike K (in press) Direct differentiation of hepatic cells from human induced pluripotent stem cells using a limited number of cytokines. Hepatol Int. doi:10.1007/s12072-011-9251–5Google Scholar
  29. Tanaka S, Toh Y, Adachi E, Matsumata T, Mori R, Sugimachi K (1993) Tumor progression in hepatocellular carcinoma may be mediated by p53 mutation. Cancer Res 53:2884–2887PubMedGoogle Scholar
  30. Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, Ebina W, Mandal PK, Smith ZD, Meissner A, Daley GQ, Brack AS, Collins JJ, Cowan C, Schlaeger TM, Rossi DJ (2010) Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7:618–630PubMedCrossRefGoogle Scholar
  31. Woltjen K, Michaell P, Mohseni P, Desai R, Mileikovsky M, Hämäläinen R, Cowling R, Wang W, Liu P, Gertsenstein M, Kaji K, Sung HK, Nagy A (2009) piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458:766–770PubMedCrossRefGoogle Scholar
  32. Wong CM, Fan ST, Ng IO (2001) Beta-catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer 92:136–145PubMedCrossRefGoogle Scholar
  33. Ye Z, Zhan H, Mali P, Dowey S, Williams DM, Jang YY, Dang CV, Spivak JL, Moliterno AR, Cheng L (2009) Human induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders. Blood 114:5473–5480PubMedCrossRefGoogle Scholar
  34. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920PubMedCrossRefGoogle Scholar
  35. Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, Thomson JA (2009) Human induced pluripotent stem cells free of vector and transgene sequences. Science 324:797–801PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Hua Liu
    • 1
  • Pooja Chaudhari
    • 1
  • Su Mi Choi
    • 1
  • Yoon-Young Jang
    • 1
  1. 1.Stem Cell Biology Laboratory, The Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreUSA

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