Autophagy regulates the apoptosis of bone marrow‐derived mesenchymal stem cells under hypoxic condition via AMP‐activated protein kinase/mammalian target of rapamycin pathway

Abstract

Bone marrow-derived mesenchymal stem cells (BM-MSCs) have been demonstrated as an ideal autologous stem cells source for cell-based therapy for myocardial infarction (MI). However, poor viability of donor stem cells after transplantation limits their therapeutic efficiency, whereas the underlying mechanism is still poorly understood. Autophagy, a highly conserved process of cellular degradation, is required for maintaining homeostasis and normal function. Here, we investigated the potential role of autophagy on apoptosis in BM-MSCs induced by hypoxic injury. BM-MSCs, isolated from male C57BL/6 mice, were subjected to hypoxia and serum deprivation (H/SD) injury for 6, 12, and 24 h, respectively. The autophagy state was regulated by 3-methyladenine (3MA) and rapamycin administration. Furthermore, compound C was administrated to inhibit AMPK. The apoptosis induced by H/SD was determined by TUNEL assays. Meanwhile, autophagy was measured by GFP-LC3 plasmids transfection and transmission electron microscope. Moreover, protein expressions were evaluated by Western blot assay. In the present study, we found that hypoxic stress increased autophagy and apoptosis in BM-MSCs time dependently. Meanwhile, hypoxia increased the activity of AMPK/mTOR signal pathway. Moreover, increased apoptosis in BM-MSCs under hypoxia was abolished by 3-MA, whereas was aggravated by rapamycin. Furthermore, the increased autophagy and apoptosis in BM-MSCs induced by hypoxia were abolished by AMPK inhibitor compound C. These data provide evidence that hypoxia induced AMPK/mTOR signal pathway activation which regulated the apoptosis and autophagy in BM-MSCs. Furthermore, the apoptosis of BM-MSCs under hypoxic condition was regulated by autophagy via AMPK/mTOR pathway.

Into the eyes of bone marrow-derived mesenchymal stem cells therapy for myocardial infarction and other diseases

“…Such discrepancy may be attributed to differences in hypoxic treatment protocol. Our previous studies adopted hypoxia (1% O 2 )/serum deprivation injury for 24 h to mimic ischemic microenvironment in vivo (43). However, Liu et al performed hypoxic preconditioning with 5% O 2 for 6 h (44).…”

“…Regulating autophagic activity may be a potential optimizing target for promoting BM-MSCs based cellular therapy for MI (43). Thus, many signaling pathways have been suggested to participate in autophagy regulation.…”

Therapeutic targeting of autophagy in myocardial infarction and heart failure

“…Likewise, inducing autophagy in bone marrow-derived mesenchymal stem cells has been proposed as an approach to increase their viability upon transplantation, and hence their therapeutic efficiency in infarcted hearts [95,96]. Interestingly, the ACMs described by Omatsu et al were also reported to have numerous autophagosomes, and their ability to develop in vitro was shown to be sensitive to pharmacological inhibition of autophagy [82].…”

Into the Eyes of Bone Marrow-Derived Mesenchymal Stem Cells Therapy for Myocardial Infarction and Other Diseases

“…Such discrepancy may be attributed to differences in hypoxic treatment protocol. Our previous studies adopted hypoxia (1% O 2 )/serum deprivation injury for 24h to mimic ischemic microenvironment in vivo [50]. However, Liu et.al.…”

“…Regulating autophagic activity may be a potential optimizing target for promoting BM-MSCs based cellular therapy for MI [50]. Thus, many signaling pathways have been suggested to participate in autophagy regulation.…”