Vascular Endothelial Growth Factor–Expressing Mesenchymal Stem Cell Transplantation for the Treatment of Acute Myocardial Infarction

Abstract

Objective-Vascular endothelial growth factor (VEGF) plays an important role in inducing angiogenesis. Mesenchymal stem cells (MSCs) may have potential for differentiation to several types of cells, including myocytes. We hypothesized that transplantation of VEGF-expressing MSCs could effectively treat acute myocardial infarction (MI) by providing enhanced cardioprotection, followed by angiogenic effects in salvaging ischemic myocardium. Methods and Results-The human VEGF 165 gene was transfected to cultured MSCs of Lewis rats using an adenoviral vector. Six million VEGF-transfected and LacZ-transfected MSCs (VEGF group), LacZ-transfected MSCs (control group), or serum-free medium only (medium group) were injected into syngeneic rat hearts 1 hour after left coronary artery occlusion. At 1 week after MI, MSCs were detected by X-gal staining in infarcted region. High expression of VEGF was immunostained in the VEGF group. At 28 days after MI, infarct size, left ventricular dimensions, ejection fraction, E wave/A wave ratio and capillary density of the infarcted region were most improved in the VEGF group, compared with the medium group. Immunohistochemically, ␣-smooth muscle actin-positive cells were most increased in the VEGF group. Key Words: angiogenesis Ⅲ gene therapy Ⅲ myocardial infarction Ⅲ stem cell Ⅲ transplantation C ell transplantation has become a promising novel therapy for ischemic heart disease and heart failure. Recent studies have revealed that various types of cells are effective in cell transplantation after myocardial infarction (MI), such as skeletal myoblasts, 1,2 smooth muscle cells, 3 and bone marrow mononuclear cells. 4 Bone marrow mononuclear cells are especially useful because they contain, among various lineage cells, hematopoietic cells and endothelial progenitor cells; therefore they have the ability to induce angiogenesis in ischemic tissue. A reported clinical trial of cell transplantation with skeletal myoblasts and mononuclear bone marrow cells showed that such therapies can have cardioprotective and angiogenic effects after MI. 5,6 However, selection of the most appropriate cell types for transplantation is controversial. Conclusions-ThisMesenchymal stem cells (MSCs) are isolated from bone marrow mononuclear cells and can be expanded ex vivo. Under appropriate culture conditions, MSCs have the potential to terminally differentiate into osteocytes, chondrocytes, adipocytes, tenocytes, myotubes, astrocytes, hematopoietic supporting stroma, and endothelial cells. 7 MSCs have also been used in a model of cell transplantation, 8,9 showing that these cells could differentiate into myogenic cells. Therefore, MSCs have many characteristics that make them useful for cellular therapy.Vascular endothelial growth factor (VEGF) is a strong therapeutic reagent for treating ischemia by inducing angiogenesis. 10 It has been reported that direct intramyocardial gene transfer results in localized enhancement of VEGF levels and successful angiogenesis in animal models of MI. 11 Furthermore, recent h...

Systems approaches to preventing transplanted cell death in cardiac repair

“…One approach to this challenge is a two-stage process, where pro-vascularization interventions are employed initially, followed by seeding of a myogenic population. In any case, vascularization is clearly required for long term graft survival, and several studies have found over-expression of vascular endothelial growth factor (VEGF) enhances grafted cell survival [74][75][76]. Interestingly, adenoviral over-expression of hypoxia inducible factor-1α (HIF-1α) [77] with grafted skeletal myoblasts increased graft cell number, blood vessel formation and cardiac function.…”

Activity of mesenchymal stem cells in therapies for chronic skin wound healing

“…Additionally, these cells have been shown to have notable immunomodulatory effects on the surrounding environment following transplantation, [29][30][31][32] and can support native cells with the secretion of a variety of pro-survival and pro-migratory cytokines and growth factors. 33,34 As a major problem in chronic wounding is unmitigated inflammation, this characteristic of MSCs has made them good candidates for approaches to cell therapy for chronic wounds in particular.…”

Proinflammatory Stem Cell Signaling in Cardiac Ischemia

“…Rat and murine MSCs overexpressing VEGF have shown improved transplanted cell survival, increased capillary density, decreased infarct size, and increased functional cardiac recovery after transplantation of these cells after ischemia (93,150). These effects appear to be greater with delivery of MSCs overexpressing VEGF than with delivery of unmodified MSCs or VEGF-containing vectors alone (44).…”