Apoptosis of bone marrow mesenchymal stromal/stem cells via the MAPK and endoplasmic reticulum stress signaling pathways

摘要

Therapy for myocardial regeneration using bone marrow stromal cells (BM-MSCs) has been applied to improve the cardiac function of subjects with acute myocardial infarction. However, the study of this therapy has encountered a bottleneck because BM-MSCs are prone to apoptosis in ischemic and anoxic environments. The goal of this study was to investigate the expression of mitogen activated protein kinase (MAPK) (p-38, JNK and ERK) and endoplasmic reticulum stress protein (caspase-12 and CHOP) during BM-MSC apoptosis. In a BM-MSC model of hypoxia and serum deprivation (H/SD), we observed the morphology and apoptotic rate of BM-MSCs for 24 h and found that the nuclear shrinkage and apoptosis rate increased gradually and reached a maximum apoptosis rate at the 6 h time point. Then, with the prolongation of the hypoxia time, the number of nuclear shrinkage cells and the apoptosis rate gradually decreased. The expression levels of p-38, JNK, ERK, procaspase-12, caspase-12 and CHOP increased at each H/SD time point. In addition, compared with the H/SD 6 h group, the nuclear shrinkage and apoptosis rate were decreased in the SB202190 and SP600125 groups but increased in the PD98059 group. Further, the expression of caspase-12 in the SB202190 group decreased, while the expression of procaspase-12 increased, compared with the H/SD 6 h group. Overall, our findings suggested that p-38, JNK, CHOP and caspase-12 play important roles in promoting the apoptosis of BM-MSCs, while ERK is contrary to other signals. Moreover, the apoptosis of BM-MSCs was induced by H/SD via the p-38-caspase-12 signaling pathway.