DNA Methyltransferases Modulate Hepatogenic Lineage Plasticity of Mesenchymal Stromal Cells

Chien Wei Lee, Wei Chih Huang, Hsien Da Huang, Yi Hsiang Huang, Jennifer H. Ho, Muh Hwa Yang, Vincent W. Yang, Oscar K. Lee

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The irreversibility of developmental processes in mammalian cells has been challenged by rising evidence that de-differentiation of hepatocytes occurs in adult liver. However, whether reversibility exists in mesenchymal stromal cell (MSC)-derived hepatocytes (dHeps) remains elusive. In this study, we find that hepatogenic differentiation (HD) of MSCs is a reversible process and is modulated by DNA methyltransferases (DNMTs). DNMTs are regulated by transforming growth factor β1 (TGFβ1), which in turn controls hepatogenic differentiation and de-differentiation. In addition, a stepwise reduction in TGFβ1 concentrations in culture media increases DNMT1 and decreases DNMT3 in primary hepatocytes (Heps) and confers Heps with multi-differentiation potentials similarly to MSCs. Hepatic lineage reversibility of MSCs and lineage conversion of Heps are regulated by DNMTs in response to TGFβ1. This previously unrecognized TGFβ1-DNMTs-MSC-HD axis may further increase the understanding the normal and pathological processes in the liver, as well as functions of MSCs after transplantation to treat liver diseases. Lee and colleagues demonstrate that through TGFβ1-regulated DNA methyltransferase axis, adult hepatocytes and MSC-derived hepatocyte-like cells can revert to an undifferentiated state without forced ectopic gene expression.

Original languageEnglish
JournalStem Cell Reports
DOIs
Publication statusPublished - 2017

    Fingerprint

Keywords

  • De-differentiation
  • DNA methyltransferases
  • Hepatocyte
  • Lineage conversion
  • Plasticity

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this