Abstract 12591: STAT3 Activation Prevents Mesenchymal Stem Cell Apoptosis and Improves Infarct Repair
The role of STAT3 in mesenchymal stem cell (MSC) biology remains unclear. We hypothesized that STAT3 activation would prevent MSC apoptosis, promote angiogenesis, and enhance infarct repair. Treatment with IL-6+epidermal growth factor (EGF) resulted in robust increase in pTyr(705)-STAT3 and STAT3-DNA binding activity in MSCs. Pretreatment with IL-6+EGF prior to 2-h hypoxia/2-h reoxygenation markedly reduced apoptotic molecular events in MSCs, indicating powerful cytoprotection. IL-6+EGF treatment increased levels of several key antiapoptotic molecules (Bcl-2, Bcl-xL, Mcl-1 [Figure], and c-FLIPS) in MSCs, indicating inhibition of both mitochondrial- and death receptor-mediated apoptosis pathways. IL-6+EGF also increased expression of VEGF, HGF, and Nkx2.5, suggesting angiogenic and cardiogenic effects of STAT3. Next, the efficacy of IL-6+EGF-induced STAT3 activation on MSC-induced cardiac repair was tested in vivo. Age-matched male wild-type (C57BL/6J) mice underwent a 30-min coronary occlusion followed by reperfusion, and 48 h later received intramyocardial injection of vehicle, untreated (control) MSCs (1 million in 30 microL), or IL-6+EGF-pretreated MSCs (1 million in 30 microL). Echocardiography was performed 4 d prior to coronary occlusion/reperfusion (BSL1) and at 48 h (BSL2), and 35 d after cell injection. After 35 d, compared with mice that received vehicle or control MSCs, mice injected with IL-6+EGF-pretreated (i.e., STAT3-activated) MSCs exhibited greater LV ejection fraction (Figure) and infarct wall thickness, indicating that STAT3 activation in MSCs results in improved infarct repair. We conclude that activation of STAT3 in MSCs by IL-6+EGF: (i) inhibits apoptosis via upregulation of multiple antiapoptotic proteins; (ii) promotes angiogenesis and cardiomyogenesis through induction of VEGF, HGF, and Nkx2.5; and (iii) improves LV structure and function after intramyocardial transplantation in vivo after a reperfused MI.
- © 2012 by American Heart Association, Inc.