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

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 journal › Article › peer-review

12 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 language	English
Pages (from-to)	247-263
Number of pages	17
Journal	Stem Cell Reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1016/j.stemcr.2017.05.008
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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10.1016/j.stemcr.2017.05.008

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@article{3775b52d73004992beaf7fcbbb69eb35,

title = "DNA Methyltransferases Modulate Hepatogenic Lineage Plasticity of Mesenchymal Stromal Cells",

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.",

keywords = "DNA methyltransferases, de-differentiation, hepatocyte, lineage conversion, plasticity",

author = "Lee, {Chien Wei} and Huang, {Wei Chih} and Huang, {Hsien Da} and Huang, {Yi Hsiang} and Ho, {Jennifer H.} and Yang, {Muh Hwa} and Yang, {Vincent W.} and Lee, {Oscar K.}",

note = "Funding Information: This work was supported in part by the Novel Bioengineering and Technological Approaches to Solve Two Major Health Problems in Taiwan sponsored by the Taiwan Ministry of Science and Technology Academic Excellence Program under grant number MOST 105-2633-B-009-003. The authors acknowledge financial support from the Ministry of Science and Technology, Taiwan (MOST103-2314-B-010-053-MY3, MOST 106-2321-B-010-008, MOST 106-2911-I-010-502, and MOST 105-2633-B-010-002). This study was also supported by Aiming for the Top University Plan, a grant from Ministry of Education. The authors also acknowledge the technical support provided by Flow Cytometry Core Facility of National Yang Ming University and Imaging Core Facility of Nanotechnology of the UST-YMU. We acknowledge Prof. Ting-Fen Tsai from National Yang-Ming University, Taiwan for the kind gift of E12.5 fetal livers and thank Prof. Chi-Chang Juan from National Yang-Ming University, Taiwan for the kind gift of FL83B cells.",

year = "2017",

doi = "10.1016/j.stemcr.2017.05.008",

language = "English",

volume = "9",

pages = "247--263",

journal = "Stem Cell Reports",

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publisher = "Cell Press",

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T1 - DNA Methyltransferases Modulate Hepatogenic Lineage Plasticity of Mesenchymal Stromal Cells

AU - Lee, Chien Wei

AU - Huang, Wei Chih

AU - Huang, Hsien Da

AU - Huang, Yi Hsiang

AU - Ho, Jennifer H.

AU - Yang, Muh Hwa

AU - Yang, Vincent W.

AU - Lee, Oscar K.

N1 - Funding Information: This work was supported in part by the Novel Bioengineering and Technological Approaches to Solve Two Major Health Problems in Taiwan sponsored by the Taiwan Ministry of Science and Technology Academic Excellence Program under grant number MOST 105-2633-B-009-003. The authors acknowledge financial support from the Ministry of Science and Technology, Taiwan (MOST103-2314-B-010-053-MY3, MOST 106-2321-B-010-008, MOST 106-2911-I-010-502, and MOST 105-2633-B-010-002). This study was also supported by Aiming for the Top University Plan, a grant from Ministry of Education. The authors also acknowledge the technical support provided by Flow Cytometry Core Facility of National Yang Ming University and Imaging Core Facility of Nanotechnology of the UST-YMU. We acknowledge Prof. Ting-Fen Tsai from National Yang-Ming University, Taiwan for the kind gift of E12.5 fetal livers and thank Prof. Chi-Chang Juan from National Yang-Ming University, Taiwan for the kind gift of FL83B cells.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - DNA methyltransferases

KW - de-differentiation

KW - hepatocyte

KW - lineage conversion

KW - plasticity

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DO - 10.1016/j.stemcr.2017.05.008

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DNA Methyltransferases Modulate Hepatogenic Lineage Plasticity of Mesenchymal Stromal Cells

Abstract

Keywords

ASJC Scopus subject areas

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Modulation of reversibility by DNA Methyltransferases during hepatogenic differentiation in Mesenchymal Stromal Cells [protein expression]

Modulation of reversibility by DNA Methyltransferases during hepatogenic differentiation in Mesenchymal Stromal Cells

Cite this

DNA Methyltransferases Modulate Hepatogenic Lineage Plasticity of Mesenchymal Stromal Cells

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Datasets

Modulation of reversibility by DNA Methyltransferases during hepatogenic differentiation in Mesenchymal Stromal Cells [protein expression]

Modulation of reversibility by DNA Methyltransferases during hepatogenic differentiation in Mesenchymal Stromal Cells

Cite this