Abstract 11150: CXCR4 Overexpressing Mesenchymal Stem Cells (MSCCR4) Enhance Their Differentiation into Endothelial Cells via STAT3 Pathway
Background: Our previous studies indicated that MSCCR4 transplantation enhanced angiogenesis after myocardial infarction (MI). In this study we sought to identify the mechanism(s) by which this result occurred.
Methods: MSC were transduced with either adenoviral-null vector (MSCNull as control) or vector encoding for overexpressing CXCR4 (MSCCR4). The MSC derived-endothelial cell (EC) differentiation was assessed by a tube formation assay, Dil-ac-LDL uptake, and EC marker expression (VE-cadherin and CD31). Gene expression was analyzed by Western blot under normoxic or hypoxic condition. In vivo study, one week after LAD ligation, a MSC patch was applied over the scarred myocardium. One month after cell implantation, echocardiography was performed and hearts were harvested for histological analysis.
Results: MSCCR4 significantly enhanced Dil-ac-LDL uptake, endothelial marker expression, and new vessel formation (Fig. 1). VE-cadherin promoter reporter activity was significantly higher in MSCCR4 than in MSCNull under hypoxia, which was blocked by WP1066, an inhibitorof STAT3. After 24 hrs hypoxia, the p-STAT3 level was significantly upregulated, and blocked after treatment of AMD3100, in MSCCR4 as compared with MSCNull. The number of endothelial cells in ischemic border zone area and heart function as measured by EF and SF were significantly higher in MSCCR4 than in MSCNull.
Conclusion: MSCCR4 enhanced neovascularization leading to improve restoration of heart function after MI by activation of STAT3 signaling pathway.
- © 2012 by American Heart Association, Inc.