Quiescence: Good and Bad of Stem Cell Aging

Tümpel, Stefan; Rudolph, K. Lenhard

doi:10.1016/j.tcb.2019.05.002

Cited by 78 publications

(67 citation statements)

References 102 publications

(140 reference statements)

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“…Notably, these processes were associated with molecular damage due to the production of toxic agents or errors in biosynthesis of macromolecules 79 80 . In line, attenuation of these activities by SC dormancy was proposed to delay SC aging 17 . Moreover, the reduced cumulating number of cell replications by quiescent SCs, may significantly attenuate the accumulation of mutations.…”

Section: Discussionmentioning

confidence: 99%

Capturing limbal epithelial stem cell population dynamics, signature, and their niche

Altshuler

Amitai-Lange

Tarazi

et al. 2020

Preprint

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AbstractStem cells (SCs) are traditionally viewed as rare, slow-cycling cells that follow deterministic rules dictating their self-renewal or differentiation. It was several decades ago, when limbal epithelial SCs (LSCs) that regenerate the corneal epithelium were one of the first sporadic, quiescent SCs ever discovered. However, LSC dynamics, heterogeneity and genetic signature are largely unknown. Moreover, recent accumulating evidence strongly suggested that epithelial SCs are actually abundant, frequently dividing cells that display stochastic behavior.In this work, we performed an in-depth analysis of the murine limbal epithelium by single-cell RNA sequencing and quantitative lineage tracing. The generated data provided an atlas of cell states of the corneal epithelial lineage, and particularly, revealed the co-existence of two novel LSC populations that reside in separate and well-defined sub-compartments. In the “outer” limbus, we identified a primitive widespread population of quiescent LSCs (qLSCs) that uniformly express Krt15/Gpha2/Ifitm3/Cd63 proteins, while the “inner” limbus host prevalent active LSCs (aLSCs) co-expressing Krt15-GFP/Atf3/Mt1-2/Socs3. Analysis of LSC population dynamics suggests that while qLSCs and aLSCs possess different proliferation rates, they both follow similar stochastic rules that dictate their self-renewal and differentiation. Finally, T cells were distributed in close proximity to qLSCs. Indeed, their absence or inhibition resulted in the loss of quiescence and delayed wound healing. Taken together, we propose that divergent regenerative strategies are tailored to properly support tissue-specific physiological constraints. The present study suggests that in the case of the cornea, quiescent epithelial SCs are abundant, follow stochastic rules and neutral drift dynamics.

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Section: Discussionmentioning

confidence: 99%

Capturing limbal epithelial stem cell population dynamics, signature, and their niche

Altshuler

Amitai-Lange

Tarazi

et al. 2020

Preprint

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“…Adult stem cells (e.g., hematopoietic stem cells, intestinal stem cells, satellite cells, skin stem cells, and germline stem cells) are implicated with the homeostasis, regeneration, and aging of practically all tissues [ 14 , 15 , 16 , 17 , 18 , 19 ]. Adult stem cell regenerative function declines with age, and cell-autonomous and non-autonomous modifications within in the niche, as well as in the circulating blood, are involved in this age-related decline [ 20 , 21 , 22 ]. In organs characterized by high and moderate turnover (like gut, bone marrow and skin), aging appears to be dictated by adult stem cell senescence [ 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease

Cianflone

Torella

Biamonte

et al. 2020

Cells

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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.

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“…Extrinsic contributions include elevated inflammation, also referred to as inflammaging, in which the increase in pro-inflammatory cytokines compromises the function of stem cells, ultimately reducing their ability to maintain homeostasis within the body. 1 Reactive oxygen species (ROS) also contribute to genetic and organelle-level damage leading to reduced stem cell function as damage can accumulate over an organism's lifetime. 2,3 Additionally, dysregulation of autophagy in stem cells can result in the buildup of critically misfolded proteins affecting stem cell potential.…”

Section: Aging Phenotypes Of Stem Cellsmentioning

confidence: 99%

Restoring aged stem cell functionality: Current progress and future directions

2020

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Stem cell dysfunction is a hallmark of aging, associated with the decline of physical and cognitive abilities of humans and other mammals [Cell 2013;153:1194]. Therefore, it has become an active area of research within the aging and stem cell fields, and various techniques have been employed to mitigate the decline of stem cell function both in vitro and in vivo. While some techniques developed in model organisms are not directly translatable to humans, others show promise in becoming clinically relevant to delay or even mitigate negative phenotypes associated with aging. This review focuses on diet, treatment, and small molecule interventions that provide evidence of functional improvement in at least one type of aged adult stem cell.

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Quiescence: Good and Bad of Stem Cell Aging

Cited by 78 publications

References 102 publications

Capturing limbal epithelial stem cell population dynamics, signature, and their niche

Capturing limbal epithelial stem cell population dynamics, signature, and their niche

Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease

Restoring aged stem cell functionality: Current progress and future directions

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