Adult Sox2+ stem cell exhaustion in mice results in cellular senescence and premature aging

Abstract

Aging is characterized by a gradual functional decline of tissues with age. Adult stem and progenitor cells are responsible for tissue maintenance, repair, and regeneration, but during aging, this population of cells is decreased or its activity is reduced, compromising tissue integrity and causing pathologies that increase vulnerability, and ultimately lead to death. The causes of stem cell exhaustion during aging are not clear, and whether a reduction in stem cell function is a cause or a consequence of aging remains unresolved. Here, we took advantage of a mouse model of induced adult Sox2+ stem cell depletion to address whether accelerated stem cell depletion can promote premature aging. After a short period of partial repetitive depletion of this adult stem cell population in mice, we observed increased kyphosis and hair graying, and reduced fat mass, all of them signs of premature aging. It is interesting that cellular senescence was identified in kidney after this partial repetitive Sox2+ cell depletion. To confirm these observations, we performed a prolonged protocol of partial repetitive depletion of Sox2+ cells, forcing regeneration from the remaining Sox2+ cells, thereby causing their exhaustion. Senescence specific staining and the analysis of the expression of genetic markers clearly corroborated that adult stem cell exhaustion can lead to cellular senescence induction and premature aging.

Ganoderic Acid D Protects Human Amniotic Mesenchymal Stem Cells against Oxidative Stress-Induced Senescence through the PERK/NRF2 Signaling Pathway

“…Adult stem cells are responsible for rejuvenating tissues by various processes, such as tissue maintenance, repair, and regeneration, throughout the life span of the higher organisms. However, a decline in their functions can lead to tissue dysfunction, organismal aging, and age-related diseases [ 3 , 4 ]. For instance, aged hematopoietic stem cells gradually lose regenerative capacity [ 5 ], impair homing and engraftment upon transplantation, accumulate signatures of widespread DNA damage [ 6 ], drive aging-associated immune remodeling [ 7 ], and lead to hematological pathologies [ 8 ].…”

High-dimensional single cell mass cytometry analysis of the murine hematopoietic system reveals signatures induced by ageing and physiological pathogen challenges

“…Ageing of the immune system is associated with increased risk of infections as well as an increased tendency towards autoimmunity and diverse immunopathologies [ 1 – 3 ]. On the one hand, physiological processes such as cellular senescence, stem and progenitor cell exhaustion as well as genomic instability may represent intrinsic key factors in age-associated alterations of the immune system [ 4 – 6 ]. On the other hand, constant challenges with pathogens and external physical stressors induce changes in the immune system [ 7 – 9 ].…”

ROS Promote Hypoxia-Induced Keratinocyte Epithelial-Mesenchymal Transition by Inducing SOX2 Expression and Subsequent Activation of Wnt/β-Catenin

“…Although it is also well known that SOX2 plays a critical role in stabilizing the pluripotency of adult stem cells [ 44 ], there is growing evidence that SOX2 positively affects cell features such as the capacity to invade and migrate and EMT [ 45 , 46 ]. Our current findings also indicated that ROS-induced activation of EMT and migration was attenuated by SOX2 silencing in cells subjected to hypoxia.…”