Restoring aged stem cell functionality: Current progress and future directions

Spehar, Kevin; Pan, Andrew; Beerman, Isabel

doi:10.1002/stem.3234

Cited by 31 publications

(29 citation statements)

References 188 publications

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“…Typically, premature aging is accompanied by hypofunction of multiple organs, vulnerable to injury and high risk of diseases. At the cellular level, accumulation of senescent cells and stem cell exhaustion are typical feature of premature aging (Kooman et al, 2014;Spehar et al, 2020). As a spectrum of intersecting signaling plays a crucial role in regulating cell longevity, any stressors causing disruption or dysregulation of these pathways would result in premature aging, such as DNA damage, oxidative stress, telomere shortening, loss of Klotho, oncogene activation (Kubben and Misteli, 2017;Opresko and Shay, 2017;Rowland et al, 2019).…”

Section: Ckd As a State Of Premature Agingmentioning

confidence: 99%

Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies

Zhou

Liu

2020

Front. Pharmacol.

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Age-related disorders such as chronic kidney disease (CKD) are increasingly prevalent globally and pose unprecedented challenges. In many aspects, CKD can be viewed as a state of accelerated and premature aging. Aging kidney and CKD share many common characteristic features with increased cellular senescence, a conserved program characterized by an irreversible cell cycle arrest with altered transcriptome and secretome. While developmental senescence and acute senescence may positively contribute to the fine-tuning of embryogenesis and injury repair, chronic senescence, when unresolved promptly, plays a crucial role in kidney fibrogenesis and CKD progression. Senescent cells elicit their fibrogenic actions primarily by secreting an assortment of inflammatory and profibrotic factors known as the senescence-associated secretory phenotype (SASP). Increasing evidence indicates that senescent cells could be a promising new target for therapeutic intervention known as senotherapy, which includes depleting senescent cells, modulating SASP and restoration of senescence inhibitors. In this review, we discuss current understanding of the role and mechanism of cellular senescence in kidney fibrosis. We also highlight potential options of targeting senescent cells for the treatment of CKD.

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Section: Ckd As a State Of Premature Agingmentioning

confidence: 99%

Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies

Zhou

Liu

2020

Front. Pharmacol.

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“…Taking into account biological significance of the proper MSCs' functioning, senescent MSCs might be considered as the crucial target for senolysis. In line with this suggestion, a number of reviews highlighting possible advantageous outcomes of senescent MSCs removal has been published over the past year [29,31,34,35]. Nevertheless, there are only few experimental data regarding this issue [36][37][38][39][40].…”

Section: Introductionmentioning

confidence: 99%

Apoptosis resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides

Deryabin

Shatrova

Borodkina

2021

Cell. Mol. Life Sci.

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Targeted elimination of senescent cells, senolysis, is one of the core trends in the anti-aging therapy. Cardiac glycosides were recently proved to be a broad-spectrum senolytics. Here we tested senolytic properties of cardiac glycosides towards human mesenchymal stem cells (hMSCs). Cardiac glycosides had no senolytic ability towards senescent hMSCs of various origins. Using biological and bioinformatic approaches we compared senescence development in ‘cardiac glycosides-sensitive’ A549 and ‘-insensitive’ hMSCs. The absence of senolysis was found to be mediated by the effective potassium import and increased apoptosis resistance in senescent hMSCs. Weakening “antiapoptotic defense” predisposes hMSCs to senolysis. We revealed that apoptosis resistance, previously recognized as a common characteristic of senescence, in fact, is not a general feature of senescent cells. Moreover, only apoptosis-prone senescent cells are sensitive to cardiac glycosides-induced senolysis. Thus, we can speculate that the effectiveness of senolysis might depend on whether senescent cells indeed become apoptosis-resistant as compared to their proliferating counterparts. Graphic abstract

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“…A number of studies have reviewed the aging process in general including protein sequestration at the nuclear periphery, and pathways of cellular proteostasis, the effects of aging on stem cell populations, and potential therapeutic interventions including that for aged HSCs [328][329][330][331][332][333][334]. Organoids have been suggested as experimental means to study the process of cellular aging [335], but much more rigorous work is needed in this area, especially with analysis ex vivo of HSCs in a relevant physioxia microenvironment BM niche model.…”

Section: J) Conclusion In Context Of Potential Future Intervention For Better Health Of the Hematopoietic System During Agingmentioning

confidence: 99%

Fate of Hematopoiesis During Aging. What Do We Really Know, and What are its Implications?

Broxmeyer

Liu

Kapur

et al. 2020

Stem Cell Rev and Rep

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There is an ongoing shift in demographics such that older persons will outnumber young persons in the coming years, and with it age-associated tissue attrition and increased diseases and disorders. There has been increased information on the association of the aging process with dysregulation of hematopoietic stem (HSC) and progenitor (HPC) cells, and hematopoiesis. This review provides an extensive up-to date summary on the literature of aged hematopoiesis and HSCs placed in context of potential artifacts of the collection and processing procedure, that may not be totally representative of the status of HSCs in their in vivo bone marrow microenvironment, and what the implications of this are for understanding aged hematopoiesis. This review covers a number of interactive areas, many of which have not been adequately explored. There are still many unknowns and mechanistic insights to be elucidated to better understand effects of aging on the hematopoietic system, efforts that will take multidisciplinary approaches, and that could lead to means to ameliorate at least some of the dysregulation of HSCs and HPCs associated with the aging process. Graphical Abstract

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Restoring aged stem cell functionality: Current progress and future directions

Cited by 31 publications

References 188 publications

Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies

Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies

Apoptosis resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides

Fate of Hematopoiesis During Aging. What Do We Really Know, and What are its Implications?

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