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

Department of Biological Science and Technology

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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 beta 1 (TGF beta 1), which in turn controls hepatogenic differentiation and de-differentiation. In addition, a stepwise reduction in TGF beta 1 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 byDNMTs in response to TGF gamma 1. This previously unrecognized TGF beta 1-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.

Original language	English
Pages (from-to)	247-263
Number of pages	7
Journal	Stem Cell Reports
Volume	9
DOIs	https://doi.org/10.1016/j.stemcr.2017.05.008
State	Published - 11 Jul 2017

Keywords

STEM-CELLS; PROGENITOR CELLS; MOUSE-LIVER; MALIGNANT-TRANSFORMATION; CHROMOSOMAL INSTABILITY; STEM/PROGENITOR CELLS; MATURE HEPATOCYTES; IN-VITRO; REGENERATION; CULTURE

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10.1016/j.stemcr.2017.05.008

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@article{a8da4f3a094c47bc8c474db32a9a6d16,

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 beta 1 (TGF beta 1), which in turn controls hepatogenic differentiation and de-differentiation. In addition, a stepwise reduction in TGF beta 1 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 byDNMTs in response to TGF gamma 1. This previously unrecognized TGF beta 1-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 = "STEM-CELLS; PROGENITOR CELLS; MOUSE-LIVER; MALIGNANT-TRANSFORMATION; CHROMOSOMAL INSTABILITY; STEM/PROGENITOR CELLS; MATURE HEPATOCYTES; IN-VITRO; REGENERATION; CULTURE",

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

year = "2017",

month = jul,

day = "11",

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

language = "English",

volume = "9",

pages = "247--263",

journal = "Stem Cell Reports",

issn = "2213-6711",

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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.

PY - 2017/7/11

Y1 - 2017/7/11

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 beta 1 (TGF beta 1), which in turn controls hepatogenic differentiation and de-differentiation. In addition, a stepwise reduction in TGF beta 1 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 byDNMTs in response to TGF gamma 1. This previously unrecognized TGF beta 1-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.

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 beta 1 (TGF beta 1), which in turn controls hepatogenic differentiation and de-differentiation. In addition, a stepwise reduction in TGF beta 1 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 byDNMTs in response to TGF gamma 1. This previously unrecognized TGF beta 1-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.

KW - STEM-CELLS; PROGENITOR CELLS; MOUSE-LIVER; MALIGNANT-TRANSFORMATION; CHROMOSOMAL INSTABILITY; STEM/PROGENITOR CELLS; MATURE HEPATOCYTES; IN-VITRO; REGENERATION; CULTURE

U2 - 10.1016/j.stemcr.2017.05.008

DO - 10.1016/j.stemcr.2017.05.008

M3 - Article

C2 - 28602611

SN - 2213-6711

VL - 9

SP - 247

EP - 263

JO - Stem Cell Reports

JF - Stem Cell Reports

ER -

DNA Methyltransferases Modulate Hepatogenic Lineage Plasticity of Mesenchymal Stromal Cells

Abstract

Keywords

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