Hypoxia regulates the therapeutic potential of mesenchymal stem cells through enhanced autophagy

Bone marrow-derived mesenchymal stem cells (BM-MSCs)have great therapeutic potential for the repair of diabetic lower-limb ischemia because of their proangiogenic properties. However, cells transplanted into an ischemic environment have reduced cell survival rates and impaired angiogenic capacity in vivo. We explored hypoxia pretreatment as a method to promote BM-MSC survival by inducing autophagy. Our results showed that hypoxic pretreatment has no effect on the phenotype or differentiation capacity of BM-MSCs; however, hypoxia increased viability and reduced apoptosis in cells treated with lipopolysaccharide. Immunofluorescence and western blot results showed that hypoxia pretreatment enhances cell autophagy mediated by elevated expression of hypoxia inducible factor-1α (HIF-1α). The AMPK/mTOR (adenosine monophosphate-activated protein kinase/mammalian target of rapamycin) signaling pathway was also activated in BM-MSCs during hypoxia-enhanced autophagy. It is important to note that hypoxia pretreatment in BM-MSCs significantly enhanced cell survival and promoted angiogenesis in the lower limb of ischemic diabetic rats. In conclusion, hypoxia pretreatment enhances survival in BM-MSCs, promoting angiogenesis by increasing autophagy and significantly decreasing apoptosis. Therefore, modulation of autophagy with hypoxic pretreatment may provide a novel strategy to improve MSC-based therapies.