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 language | English |
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Pages (from-to) | 247-263 |
Number of pages | 17 |
Journal | Stem Cell Reports |
Volume | 9 |
Issue number | 1 |
DOIs | |
Publication status | Published - 2017 |
Keywords
- DNA methyltransferases
- de-differentiation
- hepatocyte
- lineage conversion
- plasticity
ASJC Scopus subject areas
- Biochemistry
- Genetics
- Developmental Biology
- Cell Biology
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Dive into the research topics of 'DNA Methyltransferases Modulate Hepatogenic Lineage Plasticity of Mesenchymal Stromal Cells'. Together they form a unique fingerprint.Datasets
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Modulation of reversibility by DNA Methyltransferases during hepatogenic differentiation in Mesenchymal Stromal Cells [protein expression]
Huang, W. (Contributor), Huang, H. (Contributor), Yang, M. (Contributor), Yang, V. (Contributor), Lee, O. K. (Contributor), Huang, Y. (Contributor), Ho, J. H. (Contributor) & Lee, C. (Contributor), Unknown Publisher, Aug 11 2017
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE73762
Dataset
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Modulation of reversibility by DNA Methyltransferases during hepatogenic differentiation in Mesenchymal Stromal Cells
Huang, W. (Contributor), Huang, H. (Contributor), Yang, M. (Contributor), Yang, V. (Contributor), Lee, O. K. (Contributor), Huang, Y. (Contributor), Ho, J. H. (Contributor) & Lee, C. (Contributor), Unknown Publisher, Aug 11 2017
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE73617
Dataset