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PLoS One. 2019 Jun 19;14(6):e0218458. doi: 10.1371/journal.pone.0218458. eCollection 2019.

p73 regulates epidermal wound healing and induced keratinocyte programming.

Author information

1
Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, United States of America.
2
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
3
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America.
4
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.

Abstract

p63 is a transcriptional regulator of ectodermal development that is required for basal cell proliferation and stem cell maintenance. p73 is a closely related p53 family member that is expressed in select p63-positive basal cells and can heterodimerize with p63. p73-/- mice lack multiciliated cells and have reduced numbers of basal epithelial cells in select tissues; however, the role of p73 in basal epithelial cells is unknown. Herein, we show that p73-deficient mice exhibit delayed wound healing despite morphologically normal-appearing skin. The delay in wound healing is accompanied by decreased proliferation and increased levels of biomarkers of the DNA damage response in basal keratinocytes at the epidermal wound edge. In wild-type mice, this same cell population exhibited increased p73 expression after wounding. Analyzing single-cell transcriptomic data, we found that p73 was expressed by epidermal and hair follicle stem cells, cell types required for wound healing. Moreover, we discovered that p73 isoforms expressed in the skin (ΔNp73) enhance p63-mediated expression of keratinocyte genes during cellular reprogramming from a mesenchymal to basal keratinocyte-like cell. We identified a set of 44 genes directly or indirectly regulated by ΔNp73 that are involved in skin development, cell junctions, cornification, proliferation, and wound healing. Our results establish a role for p73 in cutaneous wound healing through regulation of basal keratinocyte function.

Conflict of interest statement

The authors have declared that no competing interests exist. The two co-authors currently employed by commercial companies (TMS and GLSG) performed the research associated with this study while in graduate school, prior to taking a position with a commercial company. The commercial companies have no relationship, affiliation, or association with the research in this manuscript. We can remove these current commercial affiliations if appropriate and list their affiliation at the time of their contributions to the study.

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