Adiponectin improves the therapeutic efficacy of mesenchymal stem cells by enhancing their engraftment and survival in the peri-infarct myocardium through the AMPK pathway

Poor viability of transplanted mesenchymal stem cells (MSCs) within the ischemic heart has limited their therapeutic potential for cardiac repair. We have previously shown that adiponectin (APN) treatment inhibits MSCs apoptosis under ischemic conditions in vitro. In this study, we investigated whether APN promoted the survival of MSCs in vivo and further contributed to cardiac repair in a rat model of acute myocardial infarction (AMI) by activating the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Rats were randomized into six groups: the sham, AMI control, and four other groups that were subjected to AMI followed by treatment with MSCs, APN, APN + MSCs, and APN + MSCs + AMPK inhibitor, respectively. The engraftment and survival of MSCs were detected using both immunofluorescence staining and qPCR. Cardiac function was assessed using echocardiography and left heart catheterization. H&E staining and immunohistochemical staining for MHC-II and CD206 were performed to assess the infiltration of inflammatory cells. Immunostaining for the smooth muscle cell marker alpha-smooth-muscle actin (alpha-SMA) and endothelial cell marker CD31 was performed to assess arteriogenesis and angiogenesis. APN treatment significantly enhanced the engraftment and survival rate of transplanted MSCs and further improved cardiac function and led to reduced infarct size compared with MSCs treatment alone at 4 weeks after AMI. Combined administration of APN and MSCs noticeably suppressed the inflammatory response by specifically promoting the shift of infiltrated macrophages to an less-inflammatory phenotype. Combined administration of APN and MSCs also significantly inhibited cardiomyocyte apoptosis and increased arteriogenesis and angiogenesis in the peri-infarct myocardium compared with MSCs transplantation alone. These protective effects of APN were associated with AMPK phosphorylation and were partially reversed by AMPK pathway inhibitors. Our results are the first to show that APN is able to effectively improve the survival and therapeutic efficacy of transplanted MSCs after AMI through AMPK activation. APN has the potential to be utilized for stem cell-based heart repair after AMI.

Automated summary

This study found that adiponectin (APN) can promote the survival of transplanted mesenchymal stem cells (MSCs) after acute myocardial infarction (AMI) by activating the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. APN treatment improved cardiac function, reduced infarct size, suppressed inflammation, inhibited cardiomyocyte apoptosis, and increased arteriogenesis and angiogenesis in the peri-infarct myocardium. These effects were associated with AMPK phosphorylation and partially reversed by AMPK pathway inhibitors.