Cell Stem Cell
Volume 23, Issue 4, 4 October 2018, Pages 544-556.e4
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Article
Impaired Notch Signaling Leads to a Decrease in p53 Activity and Mitotic Catastrophe in Aged Muscle Stem Cells

https://doi.org/10.1016/j.stem.2018.08.019Get rights and content
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Highlights

  • Muscle stem cells (MuSCs) tend to die by mitotic catastrophe without niche support

  • MuSC mitotic catastrophe is exacerbated by a decline in p53 associated with aging

  • Notch signaling represses Mdm2 expression, thereby increasing p53 levels in MuSCs

  • Pharmacologic enhancement of p53 levels promotes the survival of aged MuSCs

Summary

The decline of tissue regenerative potential with age correlates with impaired stem cell function. However, limited strategies are available for therapeutic modulation of stem cell function during aging. Using skeletal muscle stem cells (MuSCs) as a model system, we identify cell death by mitotic catastrophe as a cause of impaired stem cell proliferative expansion in aged animals. The mitotic cell death is caused by a deficiency in Notch activators in the microenvironment. We discover that ligand-dependent stimulation of Notch activates p53 in MuSCs via inhibition of Mdm2 expression through Hey transcription factors during normal muscle regeneration and that this pathway is impaired in aged animals. Pharmacologic activation of p53 promotes the expansion of aged MuSCs in vivo. Altogether, these findings illuminate a Notch-p53 signaling axis that plays an important role in MuSC survival during activation and is dysregulated during aging, contributing to the age-related decline in muscle regenerative potential.

Keywords

stem cells
muscle stem cells
satellite cells
muscle regeneration
aging
Notch
p53
mitotic catastrophe

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These authors contributed equally

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