Highly efficient differentiation of functional hepatocytes from human induced pluripotent stem cells

Xiaocui Ma, YuYou Duan, Benjamin Tschudy-Seney, Garrett Roll, Iman Saramipoor Behbahan, Tijess P. Ahuja, Vladimir Tolstikov, Charles Wang, Jeannine McGee, Shiva Khoobyari, Jan Nolta, Holger Willenbring, Mark A Zern

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

Human induced pluripotent stem cells (hiPSCs)hold great potential for useinregenerative medicine, novel drug development, and disease progression/developmental studies. Here, we report highly efficient differentiation of hiPSCs toward a relatively homogeneous population of functional hepa-tocytes. hiPSC-derived hepatocytes (hiHs) not only showed a high expression of hepatocyte-specific proteins and liver-specific functions, but they also developed a functional biotransformation system including phase I and II metabolizing enzymes and phase III transporters. Nuclear receptors, which are critical for regulating the expression of metabolizing enzymes, were also expressed in hiHs. hiHs also responded to different compounds/inducers ofcytochrome P450 as mature hepatocytes do. To follow up on this observation, we analyzed the drug metabolizing capacity of hiHs in real time using a novel ultraperformance liquid chromatography-tandem mass spectrometry. We found that, like freshly isolated primary human hepatocytes, the seven major metabolic pathways of the drug bufuralol were found in hiHs. In addition, transplanted hiHs engrafted, integrated, and proliferated in livers of an immune-deficient mouse model, and secreted human albumin, indicating that hiHs also function in vivo. In conclusion, we have generated a method for the efficient generation of hepatocytes from induced pluripotent stem cells in vitro and in vivo, and it appears that the cells function similarly to primary human hepatocytes, including developing a complete metabolic function. These results represent asignificant step toward using patient/disease-specific hepatocytes for cell-based therapeutics as well as for pharmacology and toxicology studies.

Original languageEnglish (US)
Pages (from-to)409-419
Number of pages11
JournalStem cells translational medicine
Volume2
Issue number6
DOIs
StatePublished - 2013

Keywords

  • Hepatocyte differentiation
  • Induced pluripotent stem cells
  • Liver regeneration
  • Stem cell transplantation

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology

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  • Cite this

    Ma, X., Duan, Y., Tschudy-Seney, B., Roll, G., Behbahan, I. S., Ahuja, T. P., Tolstikov, V., Wang, C., McGee, J., Khoobyari, S., Nolta, J., Willenbring, H., & Zern, M. A. (2013). Highly efficient differentiation of functional hepatocytes from human induced pluripotent stem cells. Stem cells translational medicine, 2(6), 409-419. https://doi.org/10.5966/sctm.2012-0160