Formation of large coronary arteries by cardiac progenitor cells

Abstract

Coronary artery disease is the most common cause of cardiac failure in the Western world, and to date there is no alternative to bypass surgery for severe coronary atherosclerosis. We report that c-kitpositive cardiac progenitor cells (CPCs) activated with insulin-like growth factor 1 and hepatocyte growth factor before their injection in proximity of the site of occlusion of the left coronary artery in rats, engrafted within the host myocardium forming temporary niches. Subsequently, CPCs divided and differentiated into endothelial cells and smooth muscle cells and, to a lesser extent, into cardiomyocytes. The acquisition of vascular lineages appeared to be mediated by the up-regulation of hypoxia-inducible factor 1␣, which promoted the synthesis and secretion of stromal-derived factor 1 from hypoxic coronary vessels. Stromal-derived factor 1 was critical in the conversion of CPCs to the vascular fate. CPCs formed conductive and intermediate-sized coronary arteries together with resistance arterioles and capillaries. The new vessels were connected with the primary coronary circulation, and this increase in vascularization more than doubled myocardial blood flow in the infarcted myocardium. This beneficial effect, together with myocardial regeneration attenuated postinfarction dilated myopathy, reduced infarct size and improved function. In conclusion, locally delivered activated CPCs generate de novo coronary vasculature and may be implemented clinically for restoration of blood supply to the ischemic myocardium.coronary blood flow ͉ infarct size ͉ myocardial regeneration ͉ stem cells ͉ vasculogenesis

Bone Marrow-Derived Human Mesenchymal Stem Cells Express Cardiomyogenic Proteins But Do Not Exhibit Functional Cardiomyogenic Differentiation Potential

“…Intensive investigations on cardiac cell biology resulted in a shift from the paradigm of the heart as a terminally differentiated postmitotic organ to a self-renewing organ [4,5]. Despite the impressive intrinsic regenerative properties of the heart mediated by, for example, resident adult cardiac progenitor cells (CPCs) [6][7][8][9], the clinical observation of fatal outcome after myocardial infarction suggests that endogenous CPCs do not effectively respond in all cases to ischemic injury. Reorganization of the damaged myocardium obviously represents the best repair mechanism; however, the natural remodeling processes of the postinfarcted heart may lead to undesired changes in the ultrastructure of the myocardium on the ionic/genomic level, the cellular level, and the extracellular matrix level [10].…”

Hydrogels for cardiac tissue engineering

“…94 Other studies have also shown in vivo differentiation of c-Kit þ stem cells to smooth muscle cells and ECs was promoted by in vitro activation of cardiac cells with insulin-like growth factor (IGF) and hepatocyte growth factor. 95 This resulted in the formation of capillaries, which were integrated with the host vasculature upon implantation. In addition, Sca-1 expressing stem cells isolated from the heart may have the capability to differentiate into cardiac cells after treatment with 5-azacytidine in vitro.…”

The effects of transplanted cells in stem cell therapy for myocardial ischemia

“…These factors induce interstitial CSCs to move through the myocardium to necrotic myocardium and scar areas. There, they divide and differentiate into heart cells and become involved in the process of new blood vessel formation (Bian et al, 2014;Hosoda et al, 2009;Tillmanns et al, 2008). CSC invasion to scar tissue is believed to be related to matrix metalloproteinase (MMP)-9 and -14 mediated regulation (Bax et al, 2012;Huang et al, 2011;Rota et al, 2008).…”