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. 2021 May;20(5):e13354.
doi: 10.1111/acel.13354. Epub 2021 Apr 9.

Age-associated expression of p21and p53 during human wound healing

Chee W Chia  1 , Cheryl A Sherman-Baust  2 , Sara A Larson  2 , Ritu Pandey  2 , Roxanne Withers  2 , Ajoy C Karikkineth  3 , Linda M Zukley  3 , Judith Campisi  4   5 , Josephine M Egan  1 , Ranjan Sen  2 , Luigi Ferrucci  6
Affiliations

Age-associated expression of p21and p53 during human wound healing

Chee W Chia et al. Aging Cell. 2021 May.

Abstract

In mice, cellular senescence and senescence-associated secretory phenotype (SASP) positively contribute to cutaneous wound healing. In this proof-of-concept study, we investigated the expressions of p16, p21, and other senescence-associated biomarkers during human wound healing in 24 healthy subjects using a double-biopsy experimental design. The first punch biopsy created the wound and established the baseline. The second biopsy, concentric to the first and taken several days after wounding, was used to probe for expression of biomarkers by immunohistochemistry and RNA FISH. To assess the effects of age, we recruited 12 sex-matched younger (30.2 ± 1.3 years) and 12 sex-matched older (75.6 ± 1.8 years) subjects. We found that p21 and p53, but not p16, were induced during healing in younger, but not older subjects. A role for Notch signaling in p21 expression was inferred from the inducible activation of HES1. Further, other SASP biomarkers such as dipeptidyl peptidase-4 (DPP4) were significantly induced upon wounding in both younger and older groups, whereas matrix metallopeptidase 9 (MMP9) was induced only in the younger group. Senescence-associated β-galactosidase (SA-β-gal) was not detectable before or after wounding. This pilot study suggests the possibility that human cutaneous wound healing is characterized by differential expression of p21 and p53 between younger and older subjects.

Keywords: aging; human wound healing; p21; p53.

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Conflict of interest statement

JC is a scientific founder of Unity Biotechnology. All other authors do not have any conflict of interest.

Figures

FIGURE 1
FIGURE 1
Representative images and quantification of p16, p21, and p53 proteins in normal skin at baseline (D0) and wounded skin (DX) (a,c,e). Brown staining in the nuclei indicates positivity for the indicated protein; expression was quantified as the number of positive cells per millimeter of epithelium (b,d,f). p16 expression was not significantly induced in response to wounding in either the younger or the older group (p = 0.08, p = 0.25) (b). p21 and p53 expressions were both significantly induced upon wounding in the younger (p < 0.001, p = 0.01), but not the older (p = 0.10, p = 0.12), groups (d,f). All images taken at 40× magnification
FIGURE 2
FIGURE 2
Representative images demonstrating CDKN1A mRNA (a), HES1 mRNA (c), and immunohistochemistry of senescence markers DPP4 (e) and MMP9 (g) in normal skin at baseline (D0) and after wounding (DX). CDKN1A mRNA signal (pseudo‐colored red); HES1 signal (pseudo‐colored green); DAPI (blue) as the nuclear stain. Each transcript is represented by a single punctum; the expression of each is represented as the average number of puncta per cell. Boxed areas are enlarged 2.5× in supplemental Figure S3. Both CDKN1A and HES1 mRNA were induced in response to wounding in the younger (p < 0.01, p < 0.001), but not the older (p = 0.10, p = 0.07) group (b,d). Images in (a) and (c) are 63X magnification. DPP4 levels (number of positive cells per millimeter of epithelium) were significantly induced in wounded skin in both the younger and older group (p < 0.01 for both) (f). MMP9 levels (proportion of positive area in the papillary dermis), in response to wounding, were significantly higher in the younger (p < 0.01) but not older (p = 0.14) group (h). Images in (e) and (g) are 40× magnification
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References

    1. Basisty, N. , Kale, A. , Jeon, O. H. , Kuehnemann, C. , Payne, T. , Rao, C. , Holtz, A. , Shah, S. , Sharma, V. , Ferrucci, L. , Campisi, J. , & Schilling, B. (2020). A proteomic atlas of senescence‐associated secretomes for aging biomarker development. PLoS Biology, 18(1), e3000599. 10.1371/journal.pbio.3000599 - DOI - PMC - PubMed
    1. Beausejour, C. M. , Krtolica, A. , Galimi, F. , Narita, M. , Lowe, S. W. , Yaswen, P. , & Campisi, J. (2003). Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO Journal, 22(16), 4212–4222. 10.1093/emboj/cdg417 - DOI - PMC - PubMed
    1. Chigurupati, S. , Arumugam, T. V. , Son, T. G. , Lathia, J. D. , Jameel, S. , Mughal, M. R. , Tang, S.‐C. , Jo, D.‐G. , Camandola, S. , Giunta, M. , Rakova, I. , McDonnell, N. , Miele, L. , Mattson, M. P. , & Poosala, S. (2007). Involvement of notch signaling in wound healing. PLoS ONE, 2(11), e1167. 10.1371/journal.pone.0001167 - DOI - PMC - PubMed
    1. Conboy, I. M. , Conboy, M. J. , Smythe, G. M. , & Rando, T. A. (2003). Notch‐mediated restoration of regenerative potential to aged muscle. Science, 302(5650), 1575. 10.1126/science.1087573 - DOI - PubMed
    1. Demaria, M. , Ohtani, N. , Youssef, S. A. , Rodier, F. , Toussaint, W. , Mitchell, J. R. , Laberge, R.‐M. , Vijg, J. , Van Steeg, H. , Dollé, M. E. T. , Hoeijmakers, J. H. J. , de Bruin, A. , Hara, E. , & Campisi, J. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF‐AA. Developmental Cell, 31(6), 722–733. 10.1016/j.devcel.2014.11.012 - DOI - PMC - PubMed

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