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.
Highlights
Several stressful insults and certain physiological processes trigger cellular senescence, which is mainly characterized by a stable and largely irreversible replicative blockage accompanied by secretory features, macromolecular damage, and deregulated metabolism [1] (Figure 1)
More than five decades ago, Leonard Hayflick demonstrated that primary human cells sub-cultivated in vitro have a limited proliferative capacity [3], such that cell cultures stop dividing after an average of 50 population doublings; this proliferation defect over time, named replicative senescence, represents the first hallmark of cellular senescence
Replicative senescence is linked to a multi-component senescence-associated secretory phenotype (SASP), which is considered the second hallmark of senescence [6,7]
Summary
Several stressful insults and certain physiological processes trigger cellular senescence, which is mainly characterized by a stable and largely irreversible replicative blockage accompanied by secretory features, macromolecular damage, and deregulated metabolism [1] (Figure 1). Senescent cells can dictate the loss of tissue homeostasis, reducing the regenerative and reparative capacity of a tissue mainly due to the functional decline of its stem cell compartment and dysregulating the normal function of adjacent cells through SASP-dependent cell-to-cell communications. Replicative senescence that results in cell cycle arrest has been generally envisioned as a highly static state that, as said above, is contrary to the highly active process related to the SASP [2]. Cell-to-cell communications—mainly through the paracrine effects of secreted factors by the SASP affecting surrounding cell and tissue—better explains the participation of cellular senescence in various physiological and pathological processes in contrast to the lone proliferative arrest [13].
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