Adult Cardiac Stem Cell Aging: A Reversible Stochastic Phenomenon?

Abstract

Aging is by far the dominant risk factor for the development of cardiovascular diseases, whose prevalence dramatically increases with increasing age reaching epidemic proportions. In the elderly, pathologic cellular and molecular changes in cardiac tissue homeostasis and response to injury result in progressive deteriorations in the structure and function of the heart. Although the phenotypes of cardiac aging have been the subject of intense study, the recent discovery that cardiac homeostasis during mammalian lifespan is maintained and regulated by regenerative events associated with endogenous cardiac stem cell (CSC) activation has produced a crucial reconsideration of the biology of the adult and aged mammalian myocardium. The classical notion of the adult heart as a static organ, in terms of cell turnover and renewal, has now been replaced by a dynamic model in which cardiac cells continuously die and are then replaced by CSC progeny differentiation. However, CSCs are not immortal. They undergo cellular senescence characterized by increased ROS production and oxidative stress and loss of telomere/telomerase integrity in response to a variety of physiological and pathological demands with aging. Nevertheless, the old myocardium preserves an endogenous functionally competent CSC cohort which appears to be resistant to the senescent phenotype occurring with aging. The latter envisions the phenomenon of CSC ageing as a result of a stochastic and therefore reversible cell autonomous process. However, CSC aging could be a programmed cell cycle-dependent process, which affects all or most of the endogenous CSC population. The latter would infer that the loss of CSC regenerative capacity with aging is an inevitable phenomenon that cannot be rescued by stimulating their growth, which would only speed their progressive exhaustion. The resolution of these two biological views will be crucial to design and develop effective CSC-based interventions to counteract cardiac aging not only improving health span of the elderly but also extending lifespan by delaying cardiovascular disease-related deaths.

Unravelling the Biology of Adult Cardiac Stem Cell-Derived Exosomes to Foster Endogenous Cardiac Regeneration and Repair

“…Since 2003, it has been reproducibly shown that the adult heart harbors a population of CSCs that participate in cardiac responses to injury and physiological CM turnover during the lifespan [11,13,14,19,21,[54][55][56][57][58]. CSCs cells are clonogenic, self-renewing and multipotent, giving rise to a minimum of three different cardiogenic cell lineages (myocytes, smooth muscle and endothelial cells) both in vitro and in vivo and exhibit significant cardiac tissue regenerative capacity [18][19][20][21].…”

Statins Stimulate New Myocyte Formation After Myocardial Infarction by Activating Growth and Differentiation of the Endogenous Cardiac Stem Cells

“…CSCs exposed to statins show a pronounced commitment to myogenesis through a balanced and very robust upregulation of myogenic transcription factors and ensuing expression of sarcomeric genes. These effects raise the potential for a similar effect on senescent CSCs in aging, where both CSC growth and differentiation are significantly impaired [3,[51][52][53][54][55]. The effects of acute exposure to statins both in vitro and in vivo remains to be shown.…”

Cardiac Fibroblast-Induced Pluripotent Stem Cell-Derived Exosomes as a Potential Therapeutic Mean for Heart Failure

“…Other studies have demonstrated that a few sub populations exist, e.g., the Lin−c-kitpos CSCs (c-kit positive cells and negative for blood/endothelial markers) that differ from other CSC and are able to differentiate not only to cardiomyocytes but also to endothelial cells and smooth muscle cells [ 12 ]. However, it has been shown that their cardio regenerative capability may be affected by different factors such as a diploid level of c-kit receptors [ 13 ], and that while they retain their cardiomyogenic potential (as can be expected from a cardiac stem cells), manipulation methods to fully use their cardio regenerative properties both in vivo and in vitro are still lacking [ 14 ].…”