Cardiac Stem Cells Possess Growth Factor-Receptor Systems That After Activation Regenerate the Infarcted Myocardium, Improving Ventricular Function and Long-Term Survival

Abstract

Abstract-Cardiac stem cells and early committed cells (CSCs-ECCs) express c-Met and insulin-like growth factor-1 (IGF-1) receptors and synthesize and secrete the corresponding ligands, hepatocyte growth factor (HGF) and IGF-1. HGF mobilizes CSCs-ECCs and IGF-1 promotes their survival and proliferation. Therefore, HGF and IGF-1 were injected in the hearts of infarcted mice to favor, respectively, the translocation of CSCs-ECCs from the surrounding myocardium to the dead tissue and the viability and growth of these cells within the damaged area. To facilitate migration and homing of CSCs-ECCs to the infarct, a growth factor gradient was introduced between the site of storage of primitive cells in the atria and the region bordering the infarct. The newly-formed myocardium contained arterioles, capillaries, and functionally competent myocytes that with time increased in size, improving ventricular performance at healing and long thereafter. The volume of regenerated myocytes was 2200 m 3 at 16 days after treatment and reached 5100 m 3 at 4 months. In this interval, nearly 20% of myocytes reached the adult phenotype, varying in size from 10 000 to 20 000 m 3 . Moreover, there were 43Ϯ13 arterioles and 155Ϯ48 capillaries/mm 2 myocardium at 16 days, and 31Ϯ6 arterioles and 390Ϯ56 capillaries at 4 months. Myocardial regeneration induced increased survival and rescued animals with infarcts that were up to 86% of the ventricle, which are commonly fatal. In conclusion, the heart has an endogenous reserve of CSCs-ECCs that can be activated to reconstitute dead myocardium and recover cardiac function. (Circ Res. 2005;97:663-673.)Key Words: cardiac progenitor cells Ⅲ myocardial regeneration Ⅲ mortality A dult cardiac stem cells (CSCs) and early committed cells (ECCs) express the stem cell antigens c-kit, MDR1, and Sca-1. 1-4 c-kit POS cells are self-renewing, clonogenic, and multipotent and give rise to myocytes, smooth muscle cells (SMCs), and endothelial cells (ECs) in vitro and in vivo. 1,5 A similar category of CSCs-ECCs has been found in the human heart, 6,7 suggesting that these undifferentiated cells participate in the normal turnover of cardiac cells and, under favorable conditions, have the ability to form myocytes, coronary arterioles, and capillary structures. 1,5,7 The presence of CSCs-ECCs raises the question of why they fail to respond to ischemic injury with regeneration of myocytes and coronary vessels and restoration of function. CSCs-ECCs distributed within the damaged area may die together with parenchymal cells, however, and SMCs and ECs in coronary vessels prevent myocardial repair. For this reason, we have explored the possibility that CSCs-ECCs, if properly activated, can translocate to sites of damage, survive the unfavorable environment, multiply, and differentiate, forming functionally competent myocardium.Hepatocyte growth factor (HGF) stimulates cell migration 8 by expression of metalloproteinases (MMPs) 9 that by breaking down the extracellular matrix favor cell locomotion, homing, and tissue reco...

Migration of Resident Cardiac Stem Cells in Myocardial Infarction

“…These cells were capable of migrating into the infarcted area from surrounding nonischemic myocardium. This process involves the SCF/c-kit and HGF/c-met pathways (Linke et al, 2005;Urbanek et al, 2005) discussed below. Bearzi et al (2007) recently reported that human c-kit þ CSCs isolated from small samples of myocardium were able to expand, and differentiate into cardiomyocytes, endothelial and smooth muscle cells in vitro.…”

“…Expression of c-met is directly regulated by HIF-1a under hypoxic conditions (Ceradini et al, 2004). Recent studies have demonstrated that HGF promotes proliferation and migration of resident c-kit þ CSC within the myocardium after MI (Linke et al, 2005;Urbanek et al, 2005). Those c-kit þ CSCs that expressed functional c-met were strongly attracted by a HGF gradient in vitro.…”

“…Moreover, intramyocardial delivery of HGF in mice enhanced migration of c-kit þ CSCs from surrounding myocardium to the infarcted region where they formed new myocytes and improved cardiac contractile function . Interestingly, the effect of HGF on migration of c-kit þ CSCs has been attributed to the expression of matrix metalloproteinases (Hamasuna et al, 1999;Urbanek et al, 2005).…”

Necrotic cell-derived high mobility group box 1 attracts antigen-presenting cells but inhibits hepatocyte growth factor-mediated tropism of mesenchymal stem cells for apoptotic cell death

“…8,9 It is cardioprotective and neuroprotective and contributes to tissue regeneration in other organs as well, partially due to anti-apoptotic, pro-angiogenic and mitogenic activities. 2,[10][11][12] Moreover, HGF attracts stem and progenitor cells, including cardiac stem cells, 13 neuronal stem cells, 14 endothelial progenitor cells 15 and mesenchymal stem cells (MSC), 4,9 which probably contributes to its tissue protective and regenerative effects.…”

Progress and prospects: Cell based regenerative therapy for cardiovascular disease

“…Recently, cardiac progenitors defined by coexpression of ckit, MDR1 and sca-1 were isolated from human hearts, 55 and in animal models of MI they were shown to be mobilized from the atria to the infarct zone after a gradient of hepatocyte growth factor and insulin-like growth factor 1 had been applied to the heart. 56,57 Another group of resident cardiac progenitor cells is characterized by the expression of the antigen 'islet 1' (isl1), and these isl1+ cells develop into cells with a mature cardiac phenotype including intact Ca 2+ -cycling and the generation of action potentials. 58 As mentioned earlier, SP cells can be isolated from the heart, and thus constitute a fifth cardiac progenitor phenotype that can acquire an adult cardiomyocyte phenotype when placed in a permissive environment.…”