Hydrogen Peroxide-Induced Senescence Reduces the Wound Healing-Promoting Effects of Mesenchymal Stem Cell-Derived Exosomes Partially via miR-146a

Mesenchymal stem cells (MSCs) have beneficial effects on wound healing.MSCs function through direct cell-cell communication or indirectly through paracrine secretion of exosomes.Here, we found that MSCderived exosomes had pro-wound healing effects via promotion of angiogenesis; however, this promoting effect was significantly reduced when senescence was induced in parental MSCs by hydrogen peroxide (H2O2).Further experiments showed that decreased miR-146a expression in exosomes derived from senescent MSCs (s-exo) contributed to these findings.In vitro, the pro-angiogenic effect of s-exo on tube formation in human umbilical vein endothelial cells was significantly reduced compared with that of exosomes derived from control MSCs (cexo).In vivo, higher tube numbers and longer tube lengths were observed in the c-exo group compared with the sexo group.Using microarray analysis, we found that miR-146a level in s-exo was lower than that in c-exo.Knockdown of miR-146a in c-exo decreased its capacity to promote angiogenesis, and overexpression of miR-146a in s-exo partially rescued its impaired pro-angiogenic capacity, thereby confirming that downregulation of miR-146a contributed to the reduced pro-wound healing capacity of s-exo.Our study is the first to demonstrate that cell senescence induced by H2O2 alters the pro-angiogenic ability of exosomes by modulating the expression of exosomal miRNAs, especially miR-146a, thus providing new insights into the correlation between parental cell state and exosome content and function.