Genetic Modification of Mesenchymal Stem Cells Overexpressing CCR1 Increases Cell Viability, Migration, Engraftment, and Capillary Density in the Injured Myocardium

Abstract

Rationale: Although mesenchymal stem cell (MSC) transplantation has been shown to promote cardiac repair in acute myocardial injury in vivo, its overall restorative capacity appears to be restricted mainly because of poor cell viability and low engraftment in the ischemic myocardium. Specific chemokines are upregulated in the infarcted myocardium. However the expression levels of the corresponding chemokine receptors (eg, CCR1, CXCR2) in MSCs are very low. We hypothesized that this discordance may account for the poor MSC engraftment and survival. Objective: To determine whether overexpression of CCR1 or CXCR2 chemokine receptors in MSCs augments their cell survival, migration and engraftment after injection in the infarcted myocardium. ver the past few years adult stromal mesenchymal stem cells have been extensively investigated for their potential in developing cell based therapies for the treatment of cardiac injury and/or other regenerative diseases. 1,2 Numerous studies have shown that transplantation of those cells in postinfarct mice decreased mortality, reduced infarct size and improved cardiac function. 2 More recently, preliminary data from a clinical study of MSCs in 69 postinfarct patients also demonstrated improved left ventricular function. 3 Despite the progress, many barriers for translating the promise of stem cell therapy into practice still exist. Homing, engraftment and survival of the transplanted cells in the ischemic area still pose major problems, with most of the cells being lost within hours of the transplantation. Moreover, the mechanisms determining these processes are still not well understood. Methods and Results: Overexpression of CCR1, but not CXCR2, dramatically increased chemokine-induced murine MSC migration and protected MSC from apoptosis in vitro. Moreover, when MSCs were injected intramyocardially one hour after coronary artery ligation, CCR1-MSCs accumulated in the infarcted myocardium at significantly higher levels than control-MSCs or CXCR2-MSCs 3 days postmyocardial infarction (MI). CCR1-MSC-injected hearts exhibited a significant reduction in infarct size, reduced cardiomyocytes apoptosis and increased capillary density in injured myocardiumChemokine induction is one of the prominent features in the postischemic heart associated with neutrophil infiltration and potential angiogenic effects. 4 Importantly, various chemokine/chemokine receptor axes are essential and potent regulators of chemotactic activities for a wide range of cell types such as monocytes and stem cells. We and others have demonstrated that many chemokines, including chemokine (c-c motif) ligand 7 (CCL7), chemokine (c-x-c motif) ligand 1 (CXCL1), chemokine (c-x-c motif) ligand 2 (CXCL2), and others were significantly upregulated in the heart following myocardial infarction (MI) and might be implicated in regulating engraftment and homing of MSCs to infarcted myocardium. [5][6][7] Although functionally active receptors for those chemokines have been identified in MSCs, their respective expression lev...

Molecular mapping of the regenerative niche in a murine model of myocardial infarction

“…Few studies have been conducted focusing on this chemokine, which has already been shown to attract MSC in migration assays as well as induced MI models (23). Furthermore, genetic modification of MSC with the CCR1 gene (CCL7 receptor) was shown to increase the viability, recruitment and retention of those cells in the MI regenerative niche (24). Plasma levels of CCL7, however, were not increased in MI patients (25).…”

Gene Therapy of the Heart through Targeting Non-Cardiac Cells

“…The beneficial effects observed on heart function, remodelling, and infarct size could have been due to increased secretion of vascular endothelial growth factor and decreased interleukin 6 levels in hearts of animals treated with genetically modified cells. Mesenchymal stem cells have also been used to overexpress the chemokine receptors CCR1 and CXCR2 before intramyocardial injection into infarcted heart (Huang et al, 2010). Stem cells with overexpression of CCR1 had increased survival intramyocardially, which was accompanied by less cardiac remodelling, increased capillarization, and improved cardiac function in both acute and chronic (4 weeks) observation times.…”

Angiopoietin-1 for Myocardial Angiogenesis

“…We therefore hypothesized that the use of bone marrow derived mesenchymal stem cells might be a better option. Mesenchymal stem cells have been extensively studied for their cardiac reparability and regenerative potential Kim et al 2010.;Labovsky et al 2010;Haider et al 2009) besides having superior transgene carrying capability Huang et al 2010;Tang et al 2010;Haider et al 2008). Besides, we also opted to replace Vegf with survival signaling molecule Akt to support survival of the genetically modified mesenchymal stem cells (Jiang et al 2006).…”