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 expansion. Understanding the process of 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, 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 senescence of hBM-MSCs and that CARM1-mediated histone H3 methylation might be the upstream regulatory mechanism controlling this function of DDR2.