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Elevated local senescence in diabetic wound healing is linked to pathological repair via CXCR2.

Wilkinson, Holly N.; Clowes, Christopher; Banyard, Kayleigh L.; Matteuci, Paolo; Mace, Kimberly; Hardman, Matthew J.

Authors

Holly N. Wilkinson

Christopher Clowes

Kayleigh L. Banyard

Paolo Matteuci

Kimberly Mace



Abstract

Cellular senescence can be broadly defined as a stable, yet essentially irreversible, loss of proliferative capacity. Historically, senescence is described as a negative outcome of advanced cellular age. It is now clear, however, that senescence represents a dynamic autonomous stress response, integral to long-term tumour suppression. Intriguingly, transient induction of a senescent phenotype has actually been suggested to promote regeneration in both liver and skin. Here we explored the role of senescence in pathological aged and diabetic murine wound healing. Aged and diabetic wounds possessed greater numbers of senescent cells, while diabetic macrophages maintained altered retention of polarisation and produced a CXCR2-enriched SASP. Of translational relevance, targeted expression of CXCR2 in primary human dermal fibroblasts led to paracrine induction of nuclear p21. Further, a selective agonist to CXCR2 was able to reverse delayed healing in diabetic mice and accelerate ex vivo human skin wound healing. Collectively these data suggest a hitherto unappreciated role for CXCR2 in mediating cellular senescence in pathological wound repair.

Journal Article Type Article
Publication Date 2019-05
Journal Journal of Investigative Dermatology
Print ISSN 0022-202x
Electronic ISSN 1523-1747
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 139
Issue 5
Pages 1171-1181.e6
Institution Citation Wilkinson, H. N., Clowes, C., Banyard, K. L., Matteuci, P., Mace, K., & Hardman, M. J. (2019). Elevated local senescence in diabetic wound healing is linked to pathological repair via CXCR2. Journal of Investigative Dermatology, 139(5), 1171-1181.e6. https://doi.org/10.1016/j.jid.2019.01.005
DOI https://doi.org/10.1016/j.jid.2019.01.005
Keywords Senescence; Wound healing; Ageing; Diabetes; Macrophage polarisation
Publisher URL https://www.sciencedirect.com/science/article/pii/S0022202X19300211?via%3Dihub#kwrds0010
Additional Information This is the accepted manuscript of an article published in Journal of investigative dermatology, 2019. The version of record is available at the DOI link in this record.

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Copyright Statement
©2019, Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/







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