Small Molecules Facilitate Single Factor-Mediated Hepatic Reprogramming

Kyung Tae Lim, Seung Chan Lee, Yimeng Gao, Kee Pyo Kim, Guangqi Song, Su Yeon An, Kenjiro Adachi, Yu Jin Jang, Jonghun Kim, Kyoung Jin Oh, Tae Hwan Kwak, Seon In Hwang, Jueng Soo You, Kinarm Ko, Seung Hoi Koo, Amar Deep Sharma, Jong Hoon Kim, Lijian Hui, Tobias Cantz, Hans R. SchölerDong Wook Han

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

Recent studies have shown that defined factors could lead to the direct conversion of fibroblasts into induced hepatocyte-like cells (iHeps). However, reported conversion efficiencies are very low, and the underlying mechanism of the direct hepatic reprogramming is largely unknown. Here, we report that direct conversion into iHeps is a stepwise transition involving the erasure of somatic memory, mesenchymal-to-epithelial transition, and induction of hepatic cell fate in a sequential manner. Through screening for additional factors that could potentially enhance the conversion kinetics, we have found that c-Myc and Klf4 (CK) dramatically accelerate conversion kinetics, resulting in remarkably improved iHep generation. Furthermore, we identified small molecules that could lead to the robust generation of iHeps without CK. Finally, we show that Hnf1α supported by small molecules is sufficient to efficiently induce direct hepatic reprogramming. This approach might help to fully elucidate the direct conversion process and also facilitate the translation of iHep into the clinic.

Original languageEnglish
Pages (from-to)814-829
Number of pages16
JournalCell Reports
Volume15
Issue number4
DOIs
Publication statusPublished - 2016 Apr 26

Keywords

  • Conversion kinetics
  • Direct conversion
  • Induced hepatocytes
  • MET

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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