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Stem Cells International Volume 2019 ,2019-07-11
Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells
Research Article
Zhenyu Xu 1 Wenming Wu 2 Fang Shen 3 Yue Yu 4 Yue Wang 5 , 6 Charlie Xiang 1
Show affiliations
DOI:10.1155/2019/7670316
Received 2018-12-27, accepted for publication 2019-05-21, Published 2019-05-21
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摘要

The application of human bone marrow mesenchymal stem cells (hBM-MSCs) in cell-based clinical therapies is hindered by the limited number of cells remaining after the initial isolation process and by cellular senescence following in vitro expansion. Understanding the process of in vitro senescence in hBM-MSCs would enable the development of strategies to maintain their vitality after cell culture. Herein, we compared the gene expression profiles of human embryonic stem cells and human BM-MSCs from donors of different ages. We first found that the expression of discoidin domain receptor 2 (DDR2) in adult donor-derived hBM-MSCs was lower than it was in the young donor-derived hBM-MSCs. Moreover, in vitro cultured late-passage hBM-MSCs showed significant downregulation of DDR2 compared to their early-passage counterparts, and siRNA inhibition of DDR2 expression recapitulated features of senescence in early-passage hBM-MSCs. Further, we found through knockdown and overexpression approaches that coactivator-associated arginine methyltransferase 1 (CARM1) regulated the expression level of DDR2 and the senescence of hBM-MSCs. Finally, chromatin immunoprecipitation analysis confirmed direct binding of CARM1 to the DDR2 promoter region with a high level of H3R17 methylation in early-passage hBM-MSCs, and inhibition of CARM1-mediated histone arginine methylation decreased DDR2 expression and led to cellular senescence. Taken together, our findings suggest that DDR2 plays a major role in regulating the in vitro senescence of hBM-MSCs and that CARM1-mediated histone H3 methylation might be the upstream regulatory mechanism controlling this function of DDR2.

授权许可

Copyright © 2019 Zhenyu Xu et al. 2019
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

通讯作者

1. Yue Yu.Department of Thyroid and Breast, Changhai Hospital, Shanghai 200433, China, chhospital.com.cn.honghelang@sohu.com
2. Yue Wang.Department of Histology and Embryology, Second Military Medical University, Shanghai 200433, China, smmu.edu.cn;Shanghai Key Laboratory of Cell Engineering, China.wangyuesmmu@163.com
3. Charlie Xiang.State Key Laboratory for Diagnosis and Treatment of Infectious Diseases and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310027, China, zju.edu.cn.cxiang@zju.edu.cn

推荐引用方式

Zhenyu Xu,Wenming Wu,Fang Shen,Yue Yu,Yue Wang,Charlie Xiang. Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells. Stem Cells International ,Vol.2019(2019)

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