Coronary vein infusion of multipotent stromal cells from bone marrow preserves cardiac function in swine ischemic cardiomyopathy via enhanced neovascularization

Abstract

Few reports have examined the effects of adult bone marrow multipotent stromal cells (MSCs) on large animals, and no useful method has been established for MSC implantation. In this study, we investigate the effects of MSC infusion from the coronary vein in a swine model of chronic myocardial infarction (MI). MI was induced in domestic swine by placing beads in the left coronary artery. Bone marrow cells were aspirated and then cultured to isolate the MSCs. At 4 weeks after MI, MSCs labeled with dye (n ¼ 8) or vehicle (n ¼ 5) were infused retrogradely from the anterior interventricular vein without any complications. Left ventriculography (LVG) was performed just before and at 4 weeks after cell infusion. The ejection fraction (EF) assessed by LVG significantly decreased from baseline up to a follow-up at 4 weeks in the control group (Po0.05), whereas the cardiac function was preserved in the MSC group. The difference in the EF between baseline and follow-up was significantly greater in the MSC group than in the control group (Po0.05). The MSC administration significantly promoted neovascularization in the border areas compared with the controls (Po0.0005), though it had no affect on cardiac fibrosis. A few MSCs expressed von Willebrand factor in a differentiation assay, but none of them expressed troponin T. In quantitative gene expression analysis, basic fibroblast growth factor and vascular endothelial growth factor (VEGF) levels were significantly higher in the MSC-treated hearts than in the controls (Po0.05, respectively). Immunohistochemical staining revealed VEGF production in the engrafted MSCs. In vitro experiment demonstrated that MSCs significantly stimulated endothelial capillary network formation compared with the VEGF protein (Po0.0001). MSC infusion via the coronary vein prevented the progression of cardiac dysfunction in chronic MI. This favorable effect appeared to derive not from cell differentiation, but from enhanced neovascularization by angiogenic factors secreted from the MSCs.

Bosentan ameliorates the expression of fibrotic related growth factors and collagen-1 in diabetic mice

“…Patients with diabetes mellitus have been shown to have poorer coronary collateral vessels, which are associated with impairment of the angiogenic response to ischemia as a result of a decrease in VEGF expression. This condition has been associated with a worsened prognosis in diabetic patients suffering from myocardial infarction (25). We observed a significant reduction in VEGF expression in all diabetic groups.…”

Stem/Progenitor-Cell-Based Approach for Restenosis after Percutaneous Coronary Intervention: Application of Bone Marrow Progenitors and Future Perspectives

“…Proangiogenic effect of MSCs: MSCs differentiated to endothelial cells in one of our earlier experiments with infarcted porcine myocardium, but the extent of differentiation was far too low to account for the significant increases in the vessel numbers [61]. MSCs express a number of proangiogenic factors, as well as proteins that modulate endothelial cell migration [55,61]. Several of these factors, such as VEGF and SDF-1, have been shown to not only induce endothelial proliferation and capillary growth, but also mobilize HSCs and EPCs from the marrow and induce them to proliferate [72].…”

“…We were also interest to find, in the same series of experiments, that MSC administration reduced the serum levels of monocyte chemoattractant protein-1 in mice fed an atherogenic diet. Proangiogenic effect of MSCs: MSCs differentiated to endothelial cells in one of our earlier experiments with infarcted porcine myocardium, but the extent of differentiation was far too low to account for the significant increases in the vessel numbers [61]. MSCs express a number of proangiogenic factors, as well as proteins that modulate endothelial cell migration [55,61].…”

“…Favorable effects of MSCs on jeopardized myocardium have been frequently reported [55][56][57][58][59][60][61][62][63]. MSCs can express phenotypic characteristics of cardiac myocytes [58].…”

“…Yet MSCs influence cardiac repair in spite of the low or transient levels of engraftment they show in vivo. We and others have shown that MSC treatment improves cardiac function in acute and chronic myocardial infarction models, in part through paracrine action [55,[60][61][62][63]. Paracrine factors released from MSCs into the surrounding tissue direct a number of restorative processes, namely, myocardial protection [60], neovascularization [61], matrix remodeling [62], and differentiation of resident progenitors [63].…”