Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells
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 i...
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| Format: | Article |
| Language: | English |
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Wiley
2019-01-01
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| Series: | Stem Cells International |
| Online Access: | http://dx.doi.org/10.1155/2019/7670316 |
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| author | Zhenyu Xu Wenming Wu Fang Shen Yue Yu Yue Wang Charlie Xiang |
| author_facet | Zhenyu Xu Wenming Wu Fang Shen Yue Yu Yue Wang Charlie Xiang |
| author_sort | Zhenyu Xu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4120412088cc4199b65547ae0c293fc5 |
| institution | Kabale University |
| issn | 1687-966X 1687-9678 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Stem Cells International |
| spelling | doaj-art-4120412088cc4199b65547ae0c293fc52025-02-03T01:12:50ZengWileyStem Cells International1687-966X1687-96782019-01-01201910.1155/2019/76703167670316Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem CellsZhenyu Xu0Wenming Wu1Fang Shen2Yue Yu3Yue Wang4Charlie Xiang5State 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, ChinaDepartment of Orthopedics, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, ChinaDepartment of Orthopaedic Surgery’s Spine Division, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, 315020, ChinaDepartment of Thyroid and Breast, Changhai Hospital, Shanghai 200433, ChinaDepartment of Histology and Embryology, Second Military Medical University, Shanghai 200433, ChinaState 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, ChinaThe 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.http://dx.doi.org/10.1155/2019/7670316 |
| spellingShingle | 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 |
| title | Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells |
| title_full | Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells |
| title_fullStr | Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells |
| title_full_unstemmed | Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells |
| title_short | Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells |
| title_sort | histone arginine methylation mediated epigenetic regulation of discoidin domain receptor 2 controls the senescence of human bone marrow mesenchymal stem cells |
| url | http://dx.doi.org/10.1155/2019/7670316 |
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