Neovascularization derived from cell transplantation in ischemic myocardium (original) (raw)
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Cardiomyocyte regeneration following angioblast-dependent neovascularization of ischemic myocardium
International Congress Series, 2004
In the adult, new blood vessel formation can occur either through angiogenesis from preexisting mature endothelium or vasculogenesis mediated by bone marrow-derived endothelial precursors. We recently isolated endothelial progenitor cells, or angioblasts, in human adult bone marrow, which have selective migratory properties for ischemic tissues, including myocardium, to where they home and induce vasculogenesis. Angioblast trafficking to the infarct zone enables development of progressively larger-sized capillaries. Here, we show that this results in sustained improvement in cardiac function by mechanisms involving induction of proliferation/regeneration of endogenous cardiomyocytes.
Endothelial progenitor cells in neovascularization of infarcted myocardium
Journal of Molecular and Cellular Cardiology, 2008
Historically, revascularization of ischemic tissue was believed to occur through the migration and proliferation of endothelial cells in nearby tissues; however, evidence accumulated in recent years indicates that a subpopulation of adult, peripheral-blood cells, collectively referred to as endothelial progenitor cells (EPCs), can differentiate into mature endothelial cells. After ischemic insult, EPCs are believed to home to sites of neovascularization, where they contribute to vascular regeneration by forming a structural component of capillaries and by secreting angiogenic factors; new evidence indicates that EPCs can also differentiate into cardiomyocytes and smooth-muscle cells. These insights into the molecular and cellular processes of tissue formation suggest that cardiac function may be preserved after myocardial infarction by transplanting EPCs into ischemic heart tissue, thereby enhancing vascular and myocardial recovery. This therapeutic strategy has been effective in animal models of ischemic disorders, and results from randomized clinical trials suggest that cell-based strategies may be safe and feasible for treatment of myocardial infarction in humans and have provided early evidence of efficacy. However, the scarcity of EPCs in the peripheral blood and evidence that several disease states reduce EPC number and/or function have prompted the development of several strategies to overcome these limitations, such as the administration of genetically modified EPCs that overexpress angiogenic growth factors. To optimize therapeutic outcomes, researchers must continue to refine methods of EPC purification, expansion, and administration, and to develop techniques that overcome the intrinsic scarcity and phenotypic deficiencies of EPCs.
Effects of cell grafting on coronary remodeling after myocardial infarction
2013
Background--With recent advances in therapeutic applications of stem cells, cell engraftment has become a promising therapy for replacing injured myocardium after infarction. The survival and function of injected cells, however, will depend on the efficient vascularization of the new tissue. Here we describe the arteriogenic remodeling of the coronary vessels that supports vascularization of engrafted tissue postmyocardial infarction (post-MI).
Cell Therapy in Ischemic Heart Disease: Interventions That Modulate Cardiac Regeneration
Stem Cells International, 2016
The incidence of severe ischemic heart disease caused by coronary obstruction has progressively increased. Alternative forms of treatment have been studied in an attempt to regenerate myocardial tissue, induce angiogenesis, and improve clinical conditions. In this context, cell therapy has emerged as a promising alternative using cells with regenerative potential, focusing on the release of paracrine and autocrine factors that contribute to cell survival, angiogenesis, and tissue remodeling. Evidence of the safety, feasibility, and potential effectiveness of cell therapy has emerged from several clinical trials using different lineages of adult stem cells. The clinical benefit, however, is not yet well established. In this review, we discuss the therapeutic potential of cell therapy in terms of regenerative and angiogenic capacity after myocardial ischemia. In addition, we addressed nonpharmacological interventions that may influence this therapeutic practice, such as diet and physi...
Therapeutic Potential of Ex Vivo Expanded Endothelial Progenitor Cells for Myocardial Ischemia
Circulation, 2001
Background-We investigated the therapeutic potential of ex vivo expanded endothelial progenitor cells (EPCs) for myocardial neovascularization. Methods and Results-Peripheral blood mononuclear cells obtained from healthy human adults were cultured in EPC medium and harvested 7 days later. Myocardial ischemia was induced by ligating the left anterior descending coronary artery in male Hsd:RH-rnu (athymic nude) rats. A total of 10 6 EPCs labeled with 1,1Ј-dioctadecyl-1 to 3,3,3Ј,3Јtetramethylindocarbocyanine perchlorate were injected intravenously 3 hours after the induction of myocardial ischemia. Seven days later, fluorescence-conjugated Bandeiraea simplicifolia lectin I was administered intravenously, and the rats were immediately killed. Fluorescence microscopy revealed that transplanted EPCs accumulated in the ischemic area and incorporated into foci of myocardial neovascularization. To determine the impact on left ventricular function, 5 rats (EPC group) were injected intravenously with 10 6 EPCs 3 hours after ischemia; 5 other rats (control group) received culture media. Echocardiography, performed just before and 28 days after ischemia, disclosed ventricular dimensions that were significantly smaller and fractional shortening that was significantly greater in the EPC group than in the control group by day 28. Regional wall motion was better preserved in the EPC group. After euthanization on day 28, necropsy examination disclosed that capillary density was significantly greater in the EPC group than in the control group. Moreover, the extent of left ventricular scarring was significantly less in rats receiving EPCs than in controls. Immunohistochemistry revealed capillaries that were positive for human-specific endothelial cells. Conclusions-Ex vivo expanded EPCs incorporate into foci of myocardial neovascularization and have a favorable impact on the preservation of left ventricular function. (Circulation. 2001;103:634-637.) Key Words: endothelium Ⅲ stem cells Ⅲ ischemia Ⅲ regeneration Ⅲ neovascularization C ollateral circulation attenuates myocardial ischemia in coronary artery disease. Recently, novel approaches that may augment collateral circulation in ischemic heart disease have been tested in preclinical and clinical studies. Gene transfer of angiogenic growth factors, for example, reportedly attenuates tissue ischemia through stimulating angiogenesis at sites of neovascularization. 1-3 Circulating CD34 antigenpositive endothelial progenitor cells (EPCs), recently isolated from the peripheral blood of adult species, 4-6 represent an alternative approach. Indeed, there is now evidence to suggest that part of the favorable impact of angiogenic growth factor therapy involves the mobilization of bone marrow-derived EPCs. 7-9 Accordingly, we transplanted ex vivo expanded EPCs in a model of rat myocardial infarction and investigated the incorporation of EPCs into sites of neovascularization, physiological indices of left ventricular (LV) function, and histological findings 4 weeks after EPC transplantation.
International Journal of Cardiology, 2014
Background: Cell-based pro-angiogenic therapy by bone marrow mesenchymal stem cells (MSCs) has been touted as a means to reducing the adverse effects of cardiac remodeling after myocardial infarction (MI). Milieu-dependent regulation of pro-angiogenic potential of MSCs after infarction remains to be elucidated. In this study, the effects of marrow-derived MSCs on the kinetics of angiogenesis signaling factors were investigated in a rabbit model of MI. Methods: MI was induced in rabbits, and the animals were randomized into two groups (cell transplantation and control, each group with 21 animals). 1 × 10 6 autologous marrow-derived MSCs were injected into the myocardium of the border zone after transfection with a green fluorescent protein (GFP) lentiviral reporter vector. Control animals received PBS vehicle only. Effect of the transplanted cells on the hearts was evaluated over time by pathological, immunofluorescence, western blotting, immuno-electron microscopy, and echocardiographic analyses. Results: Transplanted GFP-positive MSCs were enriched with time in the peri-infarct border zone with differentiation potential into three major cell types of the heart, including cardiomyocytes, endothelial cells, and smooth muscle cells, and there was significant augmentation of microvascular density. The transplanted cells could change the milieu of the injured myocardium to increase the expression levels of VEGF as well as the ratio of Ang-2 to Ang-1, and to reduce the ratio of phosphorylated Tie2 to Tie2. Conclusion: An angiogenesis-promoting milieu was induced after the transplantation of marrow MSCs in the injured myocardium. Compared with the resident cells, the transplanted cells had a greater rate of cellular kinetics in the infarcted myocardium.
European Journal of Cardio-Thoracic Surgery, 2006
The effect of transplanted mesenchymal stem cells (MSCs) on the left ventricular (LV) function and morphology in a rat myocardial infarct heart with reperfusion model were analyzed. Methods: One week after 60 min of myocardial ischemia and reperfusion by left anterior descending artery (LAD) occlusion, 1.0 Â 10 7 6-diamidino-2-phenylindole (DAPI)-labeled MSCs were injected into the infarcted myocardium and compared with controls, and sham-operated rats, in which a cell-free serum medium was injected into the infarcted region or the myocardial wall, respectively. Measurement of vascular endothelial growth factor (VEGF) expression 1 week after MSC injection using Western blot analysis (n = 5), and immunohistochemical staining using HE staining and fluorescent microscopy of the DAPI-positive regions from MSC implantation, cTnT immunostaining of potential myocardial-like cells, and SM-actin and CD31 immunostaining demonstrating neovascular transformation of implanted MSCs 1 week, 2 weeks and 4 weeks after transplantation (n = 5). Hemodynamic measurements were performed after 4 weeks in vivo. Subsequently, hearts were quickly removed and cut for histological analysis using HE staining with measurement of the infracted LV-area, the LV-wall thickness within the scar segment compared to non-infarcted scar segments, and the capillary density counting capillary vessels with 400Â light microscopy (n = 10). Results: Measurement of hemodynamics 4 weeks after transplantation in vivo showed LV function to be significantly greater in MSCs than in the control group. Semi-quantitative histomorphometric examinations showed a significantly lower infract size, a greater LV-wall thickness, and a lower Hochman-Choo expansion index in the MSC-treated group compared to the control group. Immunofluorescence demonstrated that transplanted MSCs were positive for cTnT, suggesting that a small number of transplanted MSCs can differentiate into cardiomyocytes. Other MSCs were positive for CD31 and SM-actin. The transplanted MSCs in MI area had significantly higher expression rates of cTnT, CD31 and SM-actin 2 weeks after transplantation. HE staining showed marked augmentation of neovascularization in the MSC group. Semi-quantitative analysis demonstrated that capillary density was significantly higher in the MSC group than in the control group. Conclusion: Implanted MSCs could improve cardiac structure and function through the combined effect of myogenesis and angiogenesis.
European Journal of Heart Failure, 2008
We recently isolated angiogenic cell precursors (ACPs) from human blood, which can induce angiogenesis in vitro. Aims: In the present study, we used a nude rat model of ischaemic cardiomyopathy to compare the efficacy of intramyocardial and intracoronary ACP implantation, and to evaluate effects on cardiac function, scar size and angiogenesis. Methods and results: Adult nude rats underwent coronary artery ligation. Six days later, ACPs (characterized in vitro prior to implantation) or culture media were injected directly into the ischaemic myocardial region or into the coronary artery via the aorta. Cardiac function was measured by echocardiography prior to and at 2 and 4 weeks after implantation. Scar morphology, cell engraftment, and myocardial angiogenesis were evaluated at 4 weeks. Two and four weeks after implantation, cardiac function declined in both of the control groups but improved in both the intramyocardial and intracoronary ACP groups. Significant reductions in myocardial scar area were only observed in the intramyocardial ACP group, while increases in blood vessel density, which were observed in all ACP recipients, were greatest in the intracoronary ACP group. Conclusions: Human ACPs, delivered via intramyocardial or intracoronary injection, engrafted into damaged cardiac tissue and improved cardiac function within 4 weeks through effects on scar morphology and blood vessel formation.