Decreased p53 is associated with a decline in asymmetric stem cell self‐renewal in aged human epidermis
Open Access
- 1 February 2021
- journal article
- research article
- Published by Wiley in Aging Cell
- Vol. 20 (2), e13310
- https://doi.org/10.1111/acel.13310
Abstract
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.Keywords
Funding Information
- National Institutes of Health (R21AG037032)
This publication has 56 references indexed in Scilit:
- Asymmetric cell divisions promote Notch-dependent epidermal differentiationNature, 2011
- Robust control of mitotic spindle orientation in the developing epidermisThe Journal of cell biology, 2010
- The Tumor Suppressor p53 Regulates Polarity of Self-Renewing Divisions in Mammary Stem CellsCell, 2009
- Epidermal homeostasis: a balancing act of stem cells in the skinNature Reviews Molecular Cell Biology, 2009
- p53 Regulates Hematopoietic Stem Cell QuiescenceCell Stem Cell, 2009
- Enrichment of hematopoietic stem cells with SLAM and LSK markers for the detection of hematopoietic stem cell function in normal and Trp53 null miceExperimental Hematology, 2008
- NUMB controls p53 tumour suppressor activityNature, 2008
- Declining p53 function in the aging process: A possible mechanism for the increased tumor incidence in older populationsProceedings of the National Academy of Sciences of the United States of America, 2007
- Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKα kinasesGenes & Development, 2007
- Three clonal types of keratinocyte with different capacities for multiplication.Proceedings of the National Academy of Sciences of the United States of America, 1987