Abstract
BackgroundOur previous studies indicated that MSCCXCR4 improved cardiac function after myocardial infarction (MI). This study was aimed to investigate the specific role of MSCCXCR4 in neovascularization of infarcted myocardium using a suicide gene approach.MethodsMSCs were transduced with either lentivirus-null vector/GFP (MSCNull as control) or vector encoding for overexpressing CXCR4/GFP. The MSC derived-endothelial cell (EC) differentiation was assessed by a tube formation assay, Dil-ac-LDL uptake, EC marker expression, and VE-cadherin promoter activity assay. Gene expression was analyzed by quantitative RT-PCR or Western blot. The suicide gene approach was under the control of VE-cadherin promoter. In vivo studies: Cell patches containing MSCNull or MSCCXCR4 were transduced with suicide gene and implanted into the myocardium of MI rat. Rats received either ganciclovir (GCV) or vehicle after cell implantation. After one month, the cardiac functional changes and neovascularization were assessed by echocardiography, histological analysis, and micro-CT imaging.ResultsThe expression of VEGF-A and HIF-1α was significantly higher in MSCCXCR4 as compared to MSCNull under hypoxia. Additionally, MSCCXCR4 enhanced new vessel formation and EC differentiation, as well as STAT3 phosphorylation under hypoxia. STAT3 participated in the transcription of VE-cadherin in MSCCXCR4 under hypoxia, which was inhibited by WP1066 (a STAT3 inhibitor). In addition, GCV specifically induced death of ECs with suicide gene activation. In vivo studies: MSCCXCR4 implantation promoted cardiac functional restoration, reduced infarct size, improved cardiac remodeling, and enhanced neovascularization in ischemic heart tissue. New vessels derived from MSCCXCR4 were observed at the injured heart margins and communicated with native coronary arteries. However, the derived vessel networks were reduced by GCV, reversing improvement of cardiac function.ConclusionThe transplanted MSCCXCR4 enhanced neovascularization after MI by boosting release of angiogenic factors and increasing the potential of endothelial differentiation.
Highlights
Myocardial infarction (MI) occurs when coronary blood supply is interrupted, destroying distal blood vessels and myocardium
MSCCXCR4 enhanced the expression of vascular endothelial growth factor-A (VEGF-A) and hypoxia-inducible factor-1a (HIF-1a) under hypoxia
The level of CXCR4 expression was significantly higher under normoxia in MSCCXCR4 when compared to MSCNull (p,0.05), and further increased after exposure to hypoxia for 12 to 48 hrs, which was concomitant with an increase in VEGF-A expression confirmed by Western blot (Fig. 1A and 1B)
Summary
Myocardial infarction (MI) occurs when coronary blood supply is interrupted, destroying distal blood vessels and myocardium. Therapeutic angiogenesis has been proposed as an important strategy for the treatment of vascular insufficiency in MI [1,2]. Progenitor/stem cell therapy has shown the potential to reverse ischemic damage and repair heart tissue injury through angiogenesis [3,4]. It is clinically significant to develop approaches that increase the paracrine effects or cardiovascular cell differentiation of MSCs for post-MI therapy. Considering the triple lineage differentiation potential of MSCs, the vascular cell fate decision is important to the restoration of cardiac function after MI [9]. Our previous studies indicated that MSCCXCR4 improved cardiac function after myocardial infarction (MI). This study was aimed to investigate the specific role of MSCCXCR4 in neovascularization of infarcted myocardium using a suicide gene approach
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