4.5 Article

Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium

Journal

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 44, Issue 2, Pages 281-292

Publisher

ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2007.11.010

Keywords

CXCR4 over-expression; engraftment; stem cells; myocardium infarction; matrix metalloproteinases

Funding

  1. NHLBI NIH HHS [R01 HL087861-01, R01 HL083236, HL-081859-01, HL083236, HL-74272, R01 HL087861, HL-080686, R37 HL074272, R01 HL080686, R01 HL081859, HL87861-01, R01 HL087861-02] Funding Source: Medline

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Bone marrow mesenchymal stem cells (MSCs) participate in myocardial repair following myocardial infarction. However, their in vivo reparative capability is limited due to lack of their survival in the infarcted myocardium. To overcome this limitation, we genetically engineered male rat MSCs overexpressing CXCR4 in order to maximize the effect of stromal cell-derived factor-la (SDF-1 alpha) for cell migration and regeneration. MSCs were isolated from adult male rats and cultured. Adenoviral transduction was carried out to over-express either CXCR4/green fluorescent protein (Ad-CXCR4/GFP) or Ad-null/GFP alone (control). Flow cytometry was used to identify and isolate GFP/CXCR4 overexpressing MSCs for transplantation. Female rats were assigned to one of four groups (n = 8 each) to receive GFP-transduced male MSCs (2 x 106) via tail vein injection 3 days after ligation of the left anterior descending (LAD) coronary artery: GFP-transduced MSCs (Ad-null/GFP-MSCs, group 1) or MSCs over-expressing CXCR4/GFP (Ad-CXCR4/GFP-MSCs, group 2), or Ad-CXCR4/GFP-MSCs plus SDF-1 alpha (50 ng/mu l) (Ad-CXCR4/GFP-MSCs/SDF-1 alpha, group 3), or Ad-miRNA targeting CXCR4 plus SDF-1 alpha (Ad-miRNA/GFP-MSCs+SDF-1 alpha treatment, group 4). Cardiodynamic data were obtained 4 weeks after induction of regional myocardial infarction (MI) using echocardiography after which hearts were harvested for immunohistochemical studies. The migration of GFP and Y-chromosome positive cells increased significantly in the peri- and infarct areas of groups 2 and 3 compared to control group (p < 0.05), or miRNA-CXCR4 group (p < 0.01). The number of CXCR4 positive cells in groups 2, 3 was intimately associated with angiogenesis and myogenesis. MSCs engraftment was blocked by pretreatment with miRNA (group 4). Cardiac function was significantly improved in rats receiving MSCs over-expressing CXCR4 alone or with SDF-1 alpha. The up-regulation of matrix metalloproteinases (MMPs) by CXCR4 overexpressing MSCs perhaps facilitated their engraftment in the collagenous tissue of the infarcted area. CXCR4 over-expression led to enhance in vivo mobilization and engraftment of MSCs into ischemic area where these cells promoted neomyoangiogenesis and alleviated early signs of left ventricular remodeling. (c) 2007 Elsevier Inc. All rights reserved.

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