Reprogramming induced pluripotent stem cells in the absence of c-Myc for differentiation into hepatocyte-like cells

Hsin Yang Li, Yueh Chien, Yi Jen Chen, Szu Fu Chen, Yuh Lih Chang, Chih Hung Chiang, Shaw Yeu Jeng, Chia Ming Chang, Mong Lien Wang, Liang Kung Chen, Shuen Iu Hung, Teh Ia Huo*, Shou Dong Lee, Shih Hwa Chiou

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

Induced pluripotent stem cells (iPSCs) with four reprogramming factors (Oct-4/Sox2/Klf-4/c-Myc) have been shown to differentiate into hepatic lineages. However, it was unclear whether obviation of the c-Myc oncogene in iPSCs affected hepatic differentiation or inhibited in vivo tumor formation. In this study, we demonstrated that iPSCs without c-Myc had the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) with biological functions. As detected using planar-radionuclide imaging and Hoechst labeling assays, these iPSCs and iPSC-Heps tended to mobilize to the injured liver area in thioacetamide (TAA)-treated mice. Intravenous transplantation of both iPSCs and iPSC-Heps but not mouse embryonic fibroblasts (MEFs) reduced the hepatic necrotic area, improved liver functions, and rescued TAA-treated mice from lethal acute hepatic failure (AHF). In addition, microarray-based bioinformatics and quantitative RT-PCR showed high expression of antioxidant genes in iPSCs and iPSC-Heps compared to MEFs. In vivo and in vitro studies of NAC pretreatment confirmed that iPSCs and iPSC-Heps potentially suppressed ROS production and activated antioxidant enzymes in TAA-injured livers. Six months after transplantation in TAA-treated mice, tumor formation was not seen in non-c-Myc iPSC grafts. Therefore, reprogramming adult somatic cells without c-Myc may prevent oxidative stress-induced damage and provide a safer alternative for hepatic regeneration in AHF.

Original languageEnglish
Pages (from-to)5994-6005
Number of pages12
JournalBiomaterials
Volume32
Issue number26
DOIs
StatePublished - Sep 2011

Keywords

  • Acute hepatic failure
  • Hepatocytes
  • Induced pluripotent stem cell
  • Reactive oxygen species

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