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Poor viability of transplanted mesenchymal stem cells (MSCs) within the ischemic heart has limited their therapeutic potential for cardiac repair. Adiponectin (APN) is an adipocyte-secreted adipokine with pleiotropic actions. It has recently been proposed to participate in tissue regeneration and promote the survival of several types of stem cells. This study investigated whether APN in conjunction with MSCs could improve the stem cell survival and contribute to myocardial repairs after infarction.
Sprague-Dawley rats were randomized into six groups: Sham operation; AMI control; MSCs; APN; APN + MSCs; APN + MSCs + AMPK inhibitor. MSCs labeled with CM-Dil were injected through the jugular vein in 24 hours post AMI. Globular APN were injected intraperitoneally (1 μg/g) 20 minutes after AMI. Four weeks after AMI, engraftment of MSCs to the infarcted heart was evaluated. Cardiac function was assessed using echocardiography and left heart catheterization. Apoptosis and fibrosis were measured with TUNEL and Masson's trichrome staining. Immunofluorescence was employed to examine the expression of the neovascular marker CD31 and progenitor cell marker c-kit. In vitro, MSCs were exposed to hypoxia and serum deprivation (H/SD) conditions to mimic the ischemic environment. Apoptosis was evaluated with flow cytometry and caspase-3 activity. Downstream molecules AMPK, p-AMPK, Bcl-2 and Bax were investigated using Western blot.
APN enhanced the engraftment rate of transplanted MSCs in peri-infarcted myocardium. This was accompanied by reduced apoptosis and fibrosis, as well as increased vasculogenesis. Border zone c-kit positive cells tended to be most prevalent in APN combined with MSCs treated hearts. Moreover, MSCs adjuvant with APN improved the cardiac performance compared with MSCs transplantation alone. In vitro, APN decreased the apoptosis of MSCs induced by H/SD. The protective effects of APN on MSCs survival and cardiac function were partly inhibited by AMPK inhibitor. Further, APN significantly increased the phosphorylation of AMPK in MSCs, as well as the expression of Bcl-2/Bax.
APN could improve the survival and therapeutic efficacy of transplanted MSCs through AMPK activation. This study suggests the potential application of APN for stem cell-based heart regeneration.