Resistin promotes cardiac homing of mesenchymal stem cells and functional recovery after myocardial ischemia/reperfusion via the ERK1/2-MMP-9 pathway.

BACKGROUND: Stem cell therapy is a potentially effective and promising treatment for ischemic heart disease. Resistin, a type of adipokine, has been found to bind to adipose-derived mesenchymal stem cells (ADSCs). However, the effects of resistin on cardiac homing by ADSCs and on ADSC-mediated cardioprotective effects have not been investigated.

METHODS: ADSCs were obtained from EGFP transgenic mice. C57BL/6J mice were subjected to myocardial ischemia/reperfusion (I/R) or sham operations. Six hours after the I/R operation, mice were intravenously injected with resistin-treated ADSCs (ADSC-resistin) or vehicle-treated ADSCs (ADSC-vehicle). Cardiac homing by ADSCs and cardiomyocyte apoptosis were investigated 3 days after I/R. Cardiac function, fibrosis, and angiogenesis were evaluated 4 weeks after I/R. Cellular and molecular mechanisms were investigated in vitro using cultured ADSCs.

RESULTS: Both immunostaining and flow cytometric studies showed that resistin treatment promoted ADSC myocardial homing 3 days after intravenous injection. Echocardiographic studies showed that ADSC-resistin, but not ADSC-vehicle, significantly improved the left ventricular ejection fraction (LVEF). ADSC-resistin transplantation significantly mitigated I/R-induced fibrosis and reduced ANP/BNP mRNA expression. In addition, cardiomyocyte apoptosis was reduced while angiogenesis was increased by ADSC-resistin treatment. At the cellular level, resistin promoted ADSC proliferation and migration, but did not affect H2 O2 -induced apoptosis. Molecular studies identified the ERK1/2-MMP-9 pathway as a key component mediating the effects of resistin on ADSC proliferation and migration.

CONCLUSION: These results demonstrate that resistin can promote homing of injected ADSCs into damaged heart tissue and stimulate functional recovery, an effect mediated through the ERK1/2 signaling pathway and MMP-9.