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Mesenchymal stem cells (MSCs)-based therapy provides a promising avenue for the management of peripheral arterial disease (PAD). However, engrafted MSCs are subjected to acute cell death in the ischemic microenvironment. Apelin has been shown to protect bone marrow MSCs against apoptosis although the mechanism of action remains elusive. Here we demonstrated that apelin promoted functional survival of AD-MSCs in ischemic hindlimbs and provoked a synergetic effect with AD-MSCs to restore hindlimb blood perfusion and limb functions. Further  in vitro  studies revealed that a biphasic response in autophagy was induced by apelin in AD-MSCs during hypoxia and hypoxia/reoxygenation (H/R) stages to exert cytoprotective effects against H/R injury. Mechanistically, apelin increased the viability of AD-MSCs via promoting protective autophagy during hypoxia, which was accompanied with activation of AMPK and inhibition of mammalian target of rapamycin (mTOR). To the contrary, apelin suppressed autophagic cell death during reoxygenation, which was accompanied with activation of Akt and inhibition of Beclin1. Our findings indicated that apelin facilitated AD-MSCs-based therapy in PAD, possibly through promoting survival of AD-MSCs by way of autophagy regulation. Our data support the promises of apelin as a novel strategy to improve MSC-based therapy for PAD, possibly through autophagy modulation in MSCs.

Therapeutic efficacy of apelin on transplanted mesenchymal stem cells in hindlimb ischemic mice via regulation of autophagy