Abstract 11176: Exosomes From CXCR4 Overexpressing Mesenchymal Stem Cells (MSCCR4 ) Reduce Ischemic Heart Injury via Upregulation of Paracrine Factors
Background and Objective: Exosomes secreted by MSC were shown to mediate heart infarct size. Here we examined the specific role of MSCCR4 derived exosomes on cardiac protection after myocardial infarction (MI).
Methods: Rat bone marrow-derived MSC were transduced with either lentivirus-null vector (MSCNull), or a vector encoding for CXCR4 (MSCCR4) or siRNA targeting CXCR4 (MSCsiR). In vitro: Exosomes secreted from MSC (5х105) were isolated and confirmed by transmission electron micrograph and dynamic light scattering (DLS) for both number and size distribution. (Fig.1A,B) The expression of vascular endothelial growth factor (VEGF), insulin-like growth factor 1 alpha (IGF-1α), and AKT in neonatal cardiomyocytes (Ne-C) was determined by qRT-PCR and Western blot in various groups treated with purified exosomes under normoxia or hypoxia. Apoptotic Ne-C death was detected by TUNEL assay. In vivo, one week after LAD ligation, a Ne-C patch containing exosomes derived from the 3 MSC groups was applied over scarred myocardium. After one month of Ne-C/exosome patch apposition, various parameters were analyzed.
Result: In the MSCCR4 group, as compared with the MSCNull group, TUNEL positive nuclei were significantly reduced (Fig.1 D) and the expression of VEGF, IGF-1α, and AKT was significantly upregulated after 4 hrs hypoxia (Fig.1 E and F). These salutary effects were completely blocked by LY294002, an AKT inhibitor, or by knockdown CXCR4 in MSCsiR. One month after cell/exosome graft, left ventricular fibrosis and anterior wall thickness were significantly improved in the surface of infarcted myocardium in MSCCR4 group (Fig.1 C). LV function was enhanced significantly, while infarction size and TUNEL positive nuclei were significantly reduced in MSCCR4 group as compared with any other groups(p<0.05).
Conclusion: This study reveals a novel role of exosomes derived from MSCCR4 and highlights a new mechanism of intercellular mediation of heart injury and repair after MI.
- © 2013 by American Heart Association, Inc.