Involvement of autophagy in the procedure of endoplasmic reticulum stress introduced apoptosis in bone marrow mesenchymal stem cells from nonobese diabetic mice

Abstract

Recent studies showed that bone marrow mesenchymal stem cells (BM-MSCs) from nonobese diabetic (NOD) mice exhibited the phenomenon of apoptosis. However, the mechanisms of apoptosis remained largely unknown. In this study, endoplasmic reticulum (ER) stress and autophagy were evidenced in BM-MSCs from NOD mice for the first time. We found the ER stress-mediated apoptosis was supported by the up-regulation of ER stress markers including augmented phosphorylation of phosphorylated protein kinase RNA-like ER kinase and eukaryotic translation initiator factor 2α as well as cleavage of caspase-3. Evidence of autophagy included the formation of the acidic vesicular organelles and increase of LC3 accumulation. Intriguingly, blockage of ER stress could reduce the apoptosis of BM-MSCs from NOD mice and alleviated accumulation of LC3, which indicated that ER stress induced apoptosis and autophagy. Furthermore, our results showed that the mechanism of ER stress-induced autophagy was associated with the decrease of p-S6 (a marker of mTOR activity). Here, we demonstrated that ER stress-induced cell death was mediated by autophagy that was partly attributed to the inactivation of the mammalian target of rapamycin.

Significance paragraph: We report for the first time that endoplasmic reticulum (ER) stress mediated apoptosis of bone marrow mesenchymal stem cells (BM-MSCs) from nonobese diabetic (NOD) mice. The evidence of autophagy was also found in BM-MSCs from NOD mice, included the formation of the acidic vesicular organelles and increase of LC3 accumulation. Furthermore, we demonstrated that ER stress-induced cell death was mediated by autophagy that was partly attributed to the inactivation of the mammalian target of rapamycin. Deciphering the mechanisms of ER stress signalling involved in the apoptosis of BM-MSCs from NOD mice will help improve transplantation efficacy of BM-MSCs in type 1 diabetes patients.

Keywords: apoptosis; autophagy; endoplasmic reticulum stress; mesenchymal stem cells; type 1 diabetes.