An efficient method for differentiation of human induced pluripotent stem cells into hepatocyte-like cells retaining drug metabolizing activity

Yuki Kondo, Takahiro Iwao, Katsunori Nakamura, Takamitsu Sasaki, Shogo Takahashi, Noboru Kamada, Tsutomu Matsubara, Frank J. Gonzalez, Hidenori Akutsu, Yoshitaka Miyagawa, Hajime Okita, Nobutaka Kiyokawa, Masashi Toyoda, Akihiro Umezawa, Kiyoshi Nagata, Tamihide Matsunaga, Shigeru Ohmori

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

The use of human induced pluripotent stem (iPS) cells would be of great value for a variety of applications involving drug development studies. Several reports have been published on the differentiation of human iPS cells into hepatocyte-like cells; however, the cells were insufficient for application in drug metabolism studies. In this study, we aimed to establish effective methods for differentiation of human iPS cells into hepatocytes. Two human iPS cell lines were differentiated by addition of activin A, dimethyl sulfoxide, hepatocyte growth factor, oncostatin M, and dexamethasone. The differentiated cells expressed hepatocyte markers and drug-metabolizing enzymes, revealing that the human iPS cells were differentiated into hepatocyte-like cells. Expression of CYP3A4 and UGT1A1 mRNAs increased with treatment with typical inducers of the enzymes, and the response of the cells against the inducers was similar to that of human hepatocytes. Furthermore, the drug-metabolizing activity of CYP3A4, as monitored by testosterone 6β-hydroxylase activity, was elevated by these inducers. In conclusion, we established methods for differentiation of hepatocyte-like cells expressing drug metabolizing activity from human iPS cells. The hepatocyte-like cells derived from human iPS cells will be useful for drug metabolism studies.

Original languageEnglish
Pages (from-to)237-243
Number of pages7
JournalDrug Metabolism and Pharmacokinetics
Volume29
Issue number3
DOIs
Publication statusPublished - 2014
Externally publishedYes

Fingerprint

Induced Pluripotent Stem Cells
Hepatocytes
Pharmaceutical Preparations
Cytochrome P-450 CYP3A
Oncostatin M
Hepatocyte Growth Factor
Enzymes
Helper-Inducer T-Lymphocytes
Mixed Function Oxygenases
Dimethyl Sulfoxide
Dexamethasone
Testosterone
Cell Line
Messenger RNA

Keywords

  • CYP
  • Differentiation
  • Drug-metabolizing enzyme
  • Hepatocyte
  • IPS

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Pharmaceutical Science
  • Medicine(all)

Cite this

An efficient method for differentiation of human induced pluripotent stem cells into hepatocyte-like cells retaining drug metabolizing activity. / Kondo, Yuki; Iwao, Takahiro; Nakamura, Katsunori; Sasaki, Takamitsu; Takahashi, Shogo; Kamada, Noboru; Matsubara, Tsutomu; Gonzalez, Frank J.; Akutsu, Hidenori; Miyagawa, Yoshitaka; Okita, Hajime; Kiyokawa, Nobutaka; Toyoda, Masashi; Umezawa, Akihiro; Nagata, Kiyoshi; Matsunaga, Tamihide; Ohmori, Shigeru.

In: Drug Metabolism and Pharmacokinetics, Vol. 29, No. 3, 2014, p. 237-243.

Research output: Contribution to journalArticle

Kondo, Y, Iwao, T, Nakamura, K, Sasaki, T, Takahashi, S, Kamada, N, Matsubara, T, Gonzalez, FJ, Akutsu, H, Miyagawa, Y, Okita, H, Kiyokawa, N, Toyoda, M, Umezawa, A, Nagata, K, Matsunaga, T & Ohmori, S 2014, 'An efficient method for differentiation of human induced pluripotent stem cells into hepatocyte-like cells retaining drug metabolizing activity', Drug Metabolism and Pharmacokinetics, vol. 29, no. 3, pp. 237-243. https://doi.org/10.2133/dmpk.DMPK-13-RG-104
Kondo, Yuki ; Iwao, Takahiro ; Nakamura, Katsunori ; Sasaki, Takamitsu ; Takahashi, Shogo ; Kamada, Noboru ; Matsubara, Tsutomu ; Gonzalez, Frank J. ; Akutsu, Hidenori ; Miyagawa, Yoshitaka ; Okita, Hajime ; Kiyokawa, Nobutaka ; Toyoda, Masashi ; Umezawa, Akihiro ; Nagata, Kiyoshi ; Matsunaga, Tamihide ; Ohmori, Shigeru. / An efficient method for differentiation of human induced pluripotent stem cells into hepatocyte-like cells retaining drug metabolizing activity. In: Drug Metabolism and Pharmacokinetics. 2014 ; Vol. 29, No. 3. pp. 237-243.
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