Impaired Notch Signaling Leads to a Decrease in p53 Activity and Mitotic Catastrophe in Aged Muscle Stem Cells

Liu, Ling; Charville, Gregory W.; Cheung, Tom H.; Yoo, Bryan; Santos, Pauline Joy F; Schroeder, Matthew; Rando, Thomas A.

doi:10.1016/j.stem.2018.08.019

Cited by 126 publications

(134 citation statements)

References 66 publications

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“…Similar effects are observed in other stem cell systems that have comparable dynamics to OPCs. For example, post-mitotic juvenile cardiomyocytes can be induced to proliferate by the expression of Myc (Bywater et al, 2020), while aged muscle stem cells can be rejuvenated by activation of Notch signalling, an intervention that restores their proliferation capacity and concomitantly allows for efficient differentiation of these cells (Conboy et al, 2003; Liu et al, 2018). Equally, neural stem cells become increasingly quiescent with age and stop generating new functional neurons, a process that is linked to increased inflammation and reduced mitogens, both compromising proliferation (Kalamakis et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Proliferation is a requirement for differentiation of oligodendrocyte progenitor cells during CNS remyelination

Foerster

Neumann

McClain

et al. 2020

Preprint

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SummaryOligodendrocytes that generate new myelin sheaths around demyelinated axons in the regenerative process of remyelination are generally derived from oligodendrocyte progenitor cells (OPCs). During this process, OPCs become activated, populate the area of myelin loss, and finally differentiate. Although much is known about the individual stages of remyelination, the exact sequence of events and whether a dependency of each individual stage on each other exists is unknown. Understanding the biology behind these questions is important for the development of remyelination therapies to overcome the age-related decline in remyelination efficiency observed in the chronic phase of multiple sclerosis (MS). Here we show that, following toxin-induced demyelination, all re-populating OPCs first migrate into the site of damage, undergo relatively few rounds of division and eventually differentiate. We further show that OPC proliferation is a requirement for differentiation. Together, our results reveal an unexpected link between OPC proliferation and differentiation, and opens up the possibility of novel regenerative strategies in MS focussing on stimulating OPC proliferation.

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Section: Discussionmentioning

confidence: 99%

Proliferation is a requirement for differentiation of oligodendrocyte progenitor cells during CNS remyelination

Foerster

Neumann

McClain

et al. 2020

Preprint

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“…The cells die due to mitotic catastrophe, a type of cell death associated with cell division and mitotic failure. Stabilization of p53, a well‐known tumor suppressor, rescues aged MuSCs from mitotic catastrophe both in vitro and in vivo , presumably due to its ability to lengthen the cell cycle and allow for more time to repair DNA damage …”

Section: Dynamics Of Quiescence In Muscle Stem Cellsmentioning

confidence: 99%

“…Stabilization of p53, a well-known tumor suppressor, rescues aged MuSCs from mitotic catastrophe both in vitro and in vivo, presumably due to its ability to lengthen the cell cycle and allow for more time to repair DNA damage. 29 Rando finished his talk by showing some more recent work from his laboratory in analyzing RNA transcription during MuSC activation. Most transcriptional analyses of SCs are performed after isolating and purifying cells from their niche.…”

Section: Dynamics Of Quiescence In Muscle Stem Cellsmentioning

confidence: 99%

Adult stem cells and regenerative medicine—a symposium report

Cable¹,

Fuchs

Weissman

et al. 2019

Annals of the New York Academy of Sciences

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Adult stem cells are rare, undifferentiated cells found in all tissues of the body. Although normally kept in a quiescent, nondividing state, these cells can proliferate and differentiate to replace naturally dying cells within their tissue and to repair its wounds in response to injury. Due to their proliferative nature and ability to regenerate tissue, adult stem cells have the potential to treat a variety of degenerative diseases as well as aging. In addition, since stem cells are often thought to be the source of malignant tumors, understanding the mechanisms that keep their proliferative abilities in check can pave the way for new cancer therapies. While adult stem cells have had limited practical and clinical applications to date, several clinical trials of stem cell–based therapies are underway. This report details recent research presented at the New York Academy of Sciences on March 14, 2019 on understanding the factors that regulate stem cell activity and differentiation, with the hope of translating these findings into the clinic.

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“…Skeletal muscle in aged mammals loses function, is reduced in mass, possess smaller myofibers and reduced numbers of MuSCs (Brack et al, 2005;Chakkalakal et al, 2012;Collins et al, 2007;Gibson & Schultz, 1983;Shefer et al, 2006;Sousa-Victor et al, 2014;Zhang et al, 2016). Part of the impairment of skeletal muscle with age is due to cell intrinsic deficits (Bernet et al, 2014;Cosgrove et al, 2014;Price et al, 2014;Tierney et al, 2014) and thus, the failure of skeletal muscle in aged mammals to regenerate likely arises from MuSC deficits (Bernet et al, 2014;Chakkalakal et al, 2012;Cosgrove et al, 2014;Liu et al, 2018;Pisconti et al, 2016;Zhang et al, 2016). To test if aging affects post injury MuSCs self-renewal or myonuclei generation we used EdU lineage tracing to compare MuSCs behavior in adult and aged mice.…”

Section: Post Injury Muscle Stem Cell Behavior In Aged Micementioning

confidence: 99%

“…The decline in MuSC function with age contributes to impaired muscle regeneration in aged mice and is driven by cell autonomous and non-cell autonomous mechanisms (Bernet et al, 2014;Chakkalakal, Jones, Basson, & Brack, 2012;I M Conboy et al, 2005;Cosgrove et al, 4 2014;Dumont et al, 2015;He et al, 2013;Kuswanto et al, 2016;Liu et al, 2018;Price et al, 2014;Sacco et al, 2010;Tierney et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Skeletal muscle stem cell self-renewal and differentiation kinetics revealed by EdU lineage tracing during regeneration

Pawlikowski

Antwine

et al. 2019

Preprint

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Skeletal muscle maintenance and repair is dependent on the resident adult muscle stem cell (MuSC). During injury, and in diseased muscle, stem cells are engaged to replace or repair damaged muscle, which requires the stem cells to exit quiescence and expand, followed by differentiation to regenerate myofibers and self-renewal to replenish the stem cell population.Following an injury, little is known regarding the timing of MuSC (skeletal muscle stem cell) self-renewal, myoblast expansion or myoblast differentiation. To determine the timing and kinetics of these cell fate decisions, we employed DNA-based lineage tracing to label newly replicated cells and followed cell fates during skeletal muscle regeneration. MuSCs activate and expand as myoblasts rapidly following injury, where the majority differentiate into myonuclei, establishing the centrally located myonuclear pool. Re-establishing the majority MuSC pool by self-renewal occurs after 5 days post-muscle injury, accompanied by low levels of myonuclear accretion that generate only peripheral myonuclei. In aged mice, possessing ~1/2 the number of MuSCs present in young adult mice, the timing of post injury MuSC self-renewal is delayed, and although MuSCs expansion as myoblasts in aged muscle is impaired, the number of MuSC unexpectedly recovers to young adult levels during regeneration. Following an induced muscle injury, we found that myonuclei are generated within the first four days post injury derived from myoblasts expanding from activated MuSCs. Only later during regeneration, from 5 d to 14 d post injury, is the MuSC pool replenished by self-renewal, accompanied by generation of peripheral myonuclei.

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Impaired Notch Signaling Leads to a Decrease in p53 Activity and Mitotic Catastrophe in Aged Muscle Stem Cells

Cited by 126 publications

References 66 publications

Proliferation is a requirement for differentiation of oligodendrocyte progenitor cells during CNS remyelination

Proliferation is a requirement for differentiation of oligodendrocyte progenitor cells during CNS remyelination

Adult stem cells and regenerative medicine—a symposium report

Skeletal muscle stem cell self-renewal and differentiation kinetics revealed by EdU lineage tracing during regeneration

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