Activation of Cardiac Progenitor Cells Reverses the Failing Heart Senescent Phenotype and Prolongs Lifespan

Abstract

Abstract-Heart failure is the leading cause of death in the elderly, but whether this is the result of a primary aging myopathy dictated by depletion of the cardiac progenitor cell (CPC) pool is unknown. Similarly, whether current lifespan reflects the ineluctable genetic clock or heart failure interferes with the genetically determined fate of the organ and organism is an important question. We have identified that chronological age leads to telomeric shortening in CPCs, which by necessity generate a differentiated progeny that rapidly acquires the senescent phenotype conditioning organ aging. CPC aging is mediated by attenuation of the insulin-like growth factor-1/insulin-like growth factor-1 receptor and hepatocyte growth factor/c-Met systems, which do not counteract any longer the CPC renin-angiotensin system, resulting in cellular senescence, growth arrest, and apoptosis. However, pulse-chase 5-bromodeoxyuridine-labeling assay revealed that the senescent heart contains functionally competent CPCs that have the properties of stem cells. This subset of telomerasecompetent CPCs have long telomeres and, following activation, migrate to the regions of damage, where they generate a population of young cardiomyocytes, reversing partly the aging myopathy. The senescent heart phenotype and heart failure are corrected to some extent, leading to prolongation of maximum lifespan. (Circ Res. 2008;102:597-606.)

Pharmacologic Inhibition of Cardiac Stem Cell Senescence

“…Ageing is also associated with a reduction in HGF production, thus impairing the migratory ability of CSC in response to tissue damage (Gonzalez, et al, 2008;Khan, et al, 2011); importantly, CSC dysfunction was shown to be partially restored by HGF injection (Gonzalez, et al, 2008). Regarding IGF-2-IGF2R, it has been recently demonstrated that hCSC expressing IGF-2R are characterized, with respect to IGF-1R positive hCSC, by a more senescent phenotype and by a reduced in vivo regenerative capacity (Gonzalez, et al, 2008).…”

“…Regarding IGF-2-IGF2R, it has been recently demonstrated that hCSC expressing IGF-2R are characterized, with respect to IGF-1R positive hCSC, by a more senescent phenotype and by a reduced in vivo regenerative capacity (Gonzalez, et al, 2008).…”

Telomere biology in heart failure

“…A possible source of myocytes for repopulation of the myocardium could be the pool of cardiac progenitor cells (CPCs). It has been reported that CPCs have stem cell like potential, increase in number after myocardial infarction [72], and can migrate to damaged regions of the myocardium and generate young myocytes [73]. In human failing hearts, telomeres are shorter compared to healthy, age-matched controls.…”

Cardiac Stem Cells Differentiate into Sinus Node-Like Cells

“…This discovery has dramatically changed the traditional view of all heart cells as terminally differentiated cells (Beltrami et al 2001;Bearzi et al 2007). It is greatly hoped that an improved understanding of the physiological function of CSCs will promote the development of novel therapeutic strategies (stem cell therapy) for treating heart disease and perhaps even for preventing cardiac senescence (Bearzi et al 2007;Gonzalez et al 2008;Rota et al 2008). Meanwhile, many researchers now pay great attention to biological re-establishment of cardiac pacemaker cells so as to replace electronic pacemaker for treating patients suffering from loss of cardiac pacemaker cells that results in sinus bradycardiac disorders (Miake et al 2002;Plotnikov et al 2004).…”