Insulin-Like Growth Factor-1 Receptor Identifies a Pool of Human Cardiac Stem Cells With Superior Therapeutic Potential for Myocardial Regeneration

Abstract

Rationale Age and coronary artery disease may negatively affect the function of human cardiac stem cells (hCSCs) and their potential therapeutic efficacy for autologous cell transplantation in the failing heart. Objective Insulin-like growth factor 1 (IGF-1) and 2 (IGF-2), and angiotensin II (Ang II) and their receptors, IGF-1R, IGF-2R and AT1R, were characterized in c-kit-positive-hCSCs to establish whether these systems would allow us to separate hCSC classes with different growth reserve in the aging and diseased myocardium. Methods and Results C-kit-positive-hCSCs were collected from myocardial samples obtained from 24 patients, 48 to 86 years of age, undergoing elective cardiac surgery for coronary artery disease. The expression of IGF-1R in hCSCs recognized a young cell phenotype defined by long telomeres, high telomerase activity, enhanced cell proliferation and attenuated apoptosis. In addition to IGF-1, IGF-1R-positive-hCSCs secreted IGF-2 that promoted myocyte differentiation. Conversely, the presence of IGF-2R and AT1R, in the absence of IGF-1R, identified senescent hCSCs with impaired growth reserve and increased susceptibility to apoptosis. The ability of IGF-1R-positive-hCSCs to regenerate infarcted myocardium was then compared with that of unselected c-kit-positive-hCSCs. IGF-1R-positive-hCSCs improved cardiomyogenesis and vasculogenesis. Pretreatment of IGF-1R-positive-hCSCs with IGF-2 resulted in the formation of more mature myocytes and superior recovery of ventricular structure. Conclusions hCSCs expressing only IGF-1R synthesize both IGF-1 and IGF-2, which are potent modulators of stem cell replication, commitment to the myocyte lineage and myocyte differentiation, pointing to this hCSC subset as the ideal candidate cell for the management of human heart failure.

Cellular and Molecular Characterization of Human Cardiac Stem Cells Reveals Key Features Essential for Their Function and Safety

“…It was shown that members of IGFBP family such as IGFBP4 and IGFBP3, which are independent of binding to insulin growth factor, are involved in the processes of cardiogenesis [48][49][50]. A new subset of cardiac precursor cells that expressed insulin-like growth factor 1 receptor (IGF-1R) was found to have higher proliferation and myogenic differentiation potential compared with other CSCs subgroups [51]. Overexpression of IGFBP2, which was highly expressed in our microarray results, has been reported in common brain tumors.…”

Migration of Resident Cardiac Stem Cells in Myocardial Infarction

“…Mice deficient in IGF-1 display increased apoptosis of cardiomyocytes, whereas overexpression of the IGF-1 gene inhibits apoptotic cell death after MI (Li et al, 1997;Palmen et al, 2001). The c-kit þ CSCs that express IGF-1 receptor (IGF-1R) display enhanced proliferation, differentiation, and survival in response to the IGF-1/IGF-1R interaction (Linke et al, 2005;D'Amario et al, 2011). This resulted in improvement of cardiac output, ejection fraction and the left ventricular developed pressure (LVDP) after MI (Linke et al, 2005).…”

Ex-Vivo Expansion of Cardiac Stem Cell Therapy Products for Clinical Use: The Importance of Moving towards the Optimization of Process Development

“…Most growth factors are highly cell type specific. IGF-1 or Hepatocyte Growth Factor (HGF) have been described to exert a favorable effect on human Cardiac Stem Cells rejuvenation and mobilization in the damaged or senescent heart [20,21]. Other growth factors are known to be more pleiotropic and therefore can provide positive effects on several different cell types such as Fibroblast Growth Factor-2 or Stem Cell Factor (SCF).…”