Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease

Abstract

Adult stem/progenitor are a small population of cells that reside in tissue-specific niches and possess the potential to differentiate in all cell types of the organ in which they operate. Adult stem cells are implicated with the homeostasis, regeneration, and aging of all tissues. Tissue-specific adult stem cell senescence has emerged as an attractive theory for the decline in mammalian tissue and organ function during aging. Cardiac aging, in particular, manifests as functional tissue degeneration that leads to heart failure. Adult cardiac stem/progenitor cell (CSC) senescence has been accordingly associated with physiological and pathological processes encompassing both non-age and age-related decline in cardiac tissue repair and organ dysfunction and disease. Senescence is a highly active and dynamic cell process with a first classical hallmark represented by its replicative limit, which is the establishment of a stable growth arrest over time that is mainly secondary to DNA damage and reactive oxygen species (ROS) accumulation elicited by different intrinsic stimuli (like metabolism), as well as external stimuli and age. Replicative senescence is mainly executed by telomere shortening, the activation of the p53/p16INK4/Rb molecular pathways, and chromatin remodeling. In addition, senescent cells produce and secrete a complex mixture of molecules, commonly known as the senescence-associated secretory phenotype (SASP), that regulate most of their non-cell-autonomous effects. In this review, we discuss the molecular and cellular mechanisms regulating different characteristics of the senescence phenotype and their consequences for adult CSCs in particular. Because senescent cells contribute to the outcome of a variety of cardiac diseases, including age-related and unrelated cardiac diseases like diabetic cardiomyopathy and anthracycline cardiotoxicity, therapies that target senescent cell clearance are actively being explored. Moreover, the further understanding of the reversibility of the senescence phenotype will help to develop novel rational therapeutic strategies.

Translating Evidence from Clonal Hematopoiesis to Cardiovascular Disease: A Systematic Review

“…In this scenario, an intriguing possibility is that, as CHIP originates in the HSPC compartment, resulting from HSPC clones with DNA mutations conferring them a proliferation/survival-advantage (precancerous clonal expansion), similar mutations could influence senescence, apoptosis and/or differentiation, resulting in dysfunctional tissue-specific adult stem cells contributing to cardiovascular pathology and disease. Of note, the adult mammal heart harbors resident cardiac stem/progenitor cells (CSCs) that contribute to cardiovascular pathology with age [ 94 , 95 , 96 ]. Thus, CHIP could influence and modulate the processes of cardiovascular tissue repair/regeneration of the adult heart and vasculature by affecting the immune modulation of resident stem cells and yielding a pro-fibrotic inflammatory response over reparative/regenerative tissue re-shaping.…”

“…This view widens our perspectives on the interplay between ageing, CHIP and CVD risk. In fact, ageing causes cellular and molecular changes in tissue homeostasis, and it is associated with telomere shortening as well as with a multi-component senescence-associated secretory phenotype (SASP), displaying pro-inflammatory cytokines, chemokines, extracellular matrix (ECM)-degrading proteins and other cell-cycle arrest signaling molecules [ 94 , 95 , 96 , 97 ]. All the above factors result in the progressive deterioration of the structure and function of any given organ at the tissue and cell levels [ 97 ].…”

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.…”

The Effects of Resveratrol on Telomeres and Post Myocardial Infarction Remodeling

“…Their data showed ALDH2 enzyme increased adverse cardiac remodeling and dysfunction with aging by the AMPK/SIRT1-mediated mitochondrial damage [ 15 ]. Cianflone et al reported that adult cardiac stem cells (CSC) senescence is associated with a decline in myocardial tissue repair [ 16 ]. CSC Senescence is represented by its replicative limit, which is mainly determined by telomere shortening, proper regulation of p53/p16INK4/Rb molecular pathways, chromatin remodeling [ 16 ].…”