Decreased p53 is associated with a decline in asymmetric stem cell self‐renewal in aged human epidermis. Issue 2 (1st February 2021)

• Record Type: Journal Article
• Authors: Charruyer, Alexandra; Weisenberger, Tracy; Li, Hang; Khalifa, Ayman; Schroeder, Andrew W.; Belzer, Annika; Ghadially, Ruby
• Is Part Of: Aging cell. Volume 20:Issue 2(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-02-01
• Subjects: asymmetric division -- epidermis -- keratinocyte -- p53 -- self‐renewal -- stem cell; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.13310
• Languages: English
• ISSNs: 1474-9718

Abstract

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. Abstract : Self‐renewal is decreased in aged human epidermis. Aging is associated with a shift in the balance of self‐renewal divisions toward increased symmetric and decreased asymmetric stem cell divisions. Fewer stem cells exhibit p53 expression and activity in aged versus young keratinocytes and p53 activation by Nutlin‐3 restores asymmetric stem cell self‐renewal divisions in aged keratinocytes.