Stem cell aging in adult progeria

Cheung, Hoi‐Hung; Pei, Duanqing; Chan, Wai‐Yee

doi:10.1186/s13619-015-0021-z

Cited by 6 publications

(3 citation statements)

References 95 publications

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“…However, why the defect of the causative gene WRN causes impaired regenerative capacity and overall senescence is intriguing. One explanation for this phenomenon is the accelerated depletion of the adult stem cell pool (Cheung, Pei, & Chan, ; Zhang et al, ). The availability of a human iPSC/ESC model provides a new approach to test such hypotheses.…”

Section: Discussionmentioning

confidence: 99%

Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

Wan

Zhang

et al. 2020

Aging Cell

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WRN mutation causes a premature aging disease called Werner syndrome (WS). However, the mechanism by which WRN loss leads to progeroid features evident with impaired tissue repair and regeneration remains unclear. To determine this mechanism, we performed gene editing in reprogrammed induced pluripotent stem cells (iPSCs) derived from WS fibroblasts. Gene correction restored the expression of WRN. WRN+/+ mesenchymal stem cells (MSCs) exhibited improved pro‐angiogenesis. An analysis of paracrine factors revealed that hepatocyte growth factor (HGF) was downregulated in WRN−/− MSCs. HGF insufficiency resulted in poor angiogenesis and cutaneous wound healing. Furthermore, HGF was partially regulated by PI3K/AKT signaling, which was desensitized in WRN−/− MSCs. Consistently, the inhibition of the PI3K/AKT pathway in WRN+/+ MSC resulted in reduced angiogenesis and poor wound healing. Our findings indicate that the impairment in the pro‐angiogenic function of WS‐MSCs is due to HGF insufficiency and PI3K/AKT dysregulation, suggesting trophic disruption between stromal and epithelial cells as a mechanism for WS pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

Wan

Zhang

et al. 2020

Aging Cell

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“…Healthy aging depends on the proper and persistent function of tissue-specific stem cell populations throughout the body (Ahmed et al, 2017; Oh et al, 2014). Numerous studies have shown that a variety of genetic and environmental factors can contribute to dysfunction in stem cell maintenance and self-renewal resulting in premature tissue aging (Cheung et al, 2015; Harris et al, 2018; Inomata et al, 2009; Uno and Nishida, 2016). The dormant state of cellular quiescence (G 0 ) is the primary method by which premature proliferative exhaustion of stem cell populations is prevented with age (Tümpel and Rudolph, 2019).…”

Section: Introductionmentioning

confidence: 99%

The relationship between PD-L1 and quiescence in melanocyte stem cell aging

Palmer

Villavicencio

Idris

et al. 2022

Preprint

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A central aspect of life-long stem cell function in slow cycling stem cells is the proper regulation of cellular quiescence. How the quiescent state is achieved, whether all quiescent cells are equivalent, and if the quiescent stem cell pool changes with age are all questions that remain unanswered. Using quiescent melanocyte stem cells (qMcSC) as a model, we found that stem cell quiescence is neither a singular nor static process and can be heterogeneous. As one example of this heterogeneity, we show that a portion of qMcSCs expresses the immune checkpoint protein PD-L1 at the cell membrane (PD-L1mem+), PD-L1mem+ qMcSCs are better retained with age, and that the aged quiescent McSC pool is transcriptomically more deeply quiescent. Collectively these findings demonstrate that PD-L1 expression is a physiological attribute of quiescence in McSCs and PD-L1mem+ quiescent stem cells may be good targets for reactivation in the context of aging.

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“…WRN-deficient hESCs and MSCs show phenotypes of accelerated aging including premature dysfunction such as decreased proliferative potential in addition to increased expression of p16 INK4 and p21 Waf1 , both markers of aging (Cheung et al, 2015;Shimamoto et al, 2014;Wu et al, 2018). Interestingly, WRN-depleted neuronal progenitor cells do not show signs of premature aging, neither do reprogrammed iPSCs, likely due to an increased telomerase activity as a consequence of reprogramming (will be discussed in more detail below) (Cheung et al, 2014;Shimamoto et al, 2014).…”

Section: Wrn Mutation In Stem Cell Exhaustionmentioning

confidence: 99%

Studying Werner syndrome to elucidate mechanisms and therapeutics of human aging and age-related diseases

et al. 2019

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Aging is a natural and unavoidable part of life. However, aging is also the primary driver of the dominant human diseases, such as cardiovascular disease, cancer, and neurodegenerative diseases, including Alzheimer's disease. Unraveling the sophisticated molecular mechanisms of the human aging process may provide novel strategies to extend 'healthy aging' and the cure of human aging-related diseases. Werner syndrome (WS), is a heritable human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. As a classical premature aging disease, etiological exploration of WS can shed light on the mechanisms of normal human aging and facilitate the development of interventional strategies to improve the healthspan. Here, we summarize the latest progress of the molecular understandings of WRN protein, highlight the advantages of using different WS model systems, including C. elegans, Drosophila melanogaster and induced pluripotent stem cell (iPSC) systems. Further studies on WS will propel drug development for WS patients, and possibly also for normal age-related diseases.

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Stem cell aging in adult progeria

Cited by 6 publications

References 95 publications

Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

The relationship between PD-L1 and quiescence in melanocyte stem cell aging

Studying Werner syndrome to elucidate mechanisms and therapeutics of human aging and age-related diseases

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