Decreased p53 is associated with a decline in asymmetric stem cell self-renewal in aged human epidermis.
asymmetric division
epidermis
keratinocyte
p53
self-renewal
stem cell
Journal
Aging cell
ISSN: 1474-9726
Titre abrégé: Aging Cell
Pays: England
ID NLM: 101130839
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
21
08
2019
revised:
26
10
2020
accepted:
01
12
2020
pubmed:
2
2
2021
medline:
7
9
2021
entrez:
1
2
2021
Statut:
ppublish
Résumé
With age, the epidermis becomes hypoplastic and hypoproliferative. Hypoproliferation due to aging has been associated with decreased stem cell (SC) self-renewal in multiple murine tissues. The fate of SC self-renewal divisions can be asymmetric (one SC, one committed progenitor) or symmetric (two SCs). Increased asymmetric SC self-renewal has been observed in inflammatory-mediated hyperproliferation, while increased symmetric SC self-renewal has been observed in cancers. We analyzed SC self-renewal divisions in aging human epidermis to better understand the role of SCs in the hypoproliferation of aging. In human subjects, neonatal to 78 years, there was an age-dependent decrease in epidermal basal layer divisions. The balance of SC self-renewal shifted toward symmetric SC self-renewal, with a decline in asymmetric SC self-renewal. Asymmetric SC divisions maintain epidermal stratification, and this decrease may contribute to the hypoplasia of aging skin. P53 decreases in multiple tissues with age, and p53 has been shown to promote asymmetric SC self-renewal. Fewer aged than adult ALDH+CD44+ keratinocyte SCs exhibited p53 expression and activity and Nutlin-3 (a p53 activator) returned p53 activity as well as asymmetric SC self-renewal divisions to adult levels. Nutlin-3 increased Notch signaling (NICD, Hes1) and DAPT inhibition of Notch activation prevented Nutlin-3 (p53)-induced asymmetric SC self-renewal divisions in aged keratinocytes. These studies indicate a role for p53 in the decreased asymmetric SC divisions with age and suggest that in aged keratinocytes, Notch is required for p53-induced asymmetric SC divisions.
Identifiants
pubmed: 33524216
doi: 10.1111/acel.13310
pmc: PMC7884041
doi:
Substances chimiques
Imidazoles
0
Piperazines
0
Tumor Suppressor Protein p53
0
nutlin 3
53IA0V845C
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13310Subventions
Organisme : NCI NIH HHS
ID : P30 CA082103
Pays : United States
Organisme : Merit Review Award
ID : BX000794
Organisme : NIH HHS
ID : R21AG037032
Pays : United States
Informations de copyright
© 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
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