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

doi:10.1016/j.stemcr.2017.05.008

DNA Methyltransferases Modulate Hepatogenic Lineage Plasticity of Mesenchymal Stromal Cells

Stem Cell Reports. 2017 Jul 11;9(1):247-263. doi: 10.1016/j.stemcr.2017.05.008. Epub 2017 Jun 8.

Authors

Chien-Wei Lee¹, Wei-Chih Huang², Hsien-Da Huang³, Yi-Hsiang Huang⁴, Jennifer H Ho⁵, Muh-Hwa Yang⁶, Vincent W Yang⁷, Oscar K Lee⁸

Affiliations

¹ Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 11221, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
² Institute of Bioinformatics and Systems Biology, National Chiao Tung University, HsinChu 30010, Taiwan.
³ Institute of Bioinformatics and Systems Biology, National Chiao Tung University, HsinChu 30010, Taiwan; Department of Biological Science and Technology, National Chiao Tung University, HsinChu 30010, Taiwan; Center for Bioinformatics Research, National Chiao Tung University, HsinChu 30010, Taiwan; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁴ Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11221, Taiwan.
⁵ Center for Stem Cell Research, Taipei Medical University-Wan Fang Hospital, Taipei 11031, Taiwan.
⁶ Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei 11221, Taiwan; Genome Research Center, National Yang-Ming University, Taipei 11221, Taiwan; Immunity and Inflammation Research Center, National Yang-Ming University, Taipei 11221, Taiwan; Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
⁷ Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
⁸ Taipei City Hospital, Taipei 10341, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan; Stem Cell Research Center, National Yang-Ming University, Taipei 11221, Taiwan; Department of Medical Research, Taipei Veterans General Hospital, Taipei 11221, Taiwan. Electronic address: [email protected].

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.

Keywords: DNA methyltransferases; de-differentiation; hepatocyte; lineage conversion; plasticity.

MeSH terms

Animals
Cell Differentiation*
Cell Lineage
Cells, Cultured
DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
DNA (Cytosine-5-)-Methyltransferases / metabolism
DNA Methyltransferase 3A
DNA Modification Methylases / metabolism*
Hepatocytes / cytology*
Humans
Liver / cytology
Liver / metabolism
Mesenchymal Stem Cells / cytology*
Mesenchymal Stem Cells / metabolism
Mice
Signal Transduction
Transforming Growth Factor beta / metabolism

Substances

DNMT3A protein, human
Transforming Growth Factor beta
DNA Modification Methylases
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases
DNA Methyltransferase 3A