An analysis of replicative senescence in dermal fibroblasts derived from chronic leg wounds predicts that telomerase therapy would fail to reverse their disease-specific cellular and proteolytic phenotype

Stephens, Philip ORCID: https://orcid.org/0000-0002-0840-4996, Cook, Helen, Hilton, Joanne, Jones, Christopher John, Haughton, Michele Fleur, Wyllie, Fiona Sandra, Skinner, Julia W., Harding, Keith Gordon, Kipling, David Glyn and Thomas, David William ORCID: https://orcid.org/0000-0001-7319-5820 2003. An analysis of replicative senescence in dermal fibroblasts derived from chronic leg wounds predicts that telomerase therapy would fail to reverse their disease-specific cellular and proteolytic phenotype. Experimental Cell Research 283 (1) , pp. 22-35. 10.1016/S0014-4827(02)00021-6

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Abstract

The accumulation of senescent fibroblasts within tissues has been suggested to play an important role in mediating impaired dermal wound healing, which is a major clinical problem in the aged population. The concept that replicative senescence in wound fibroblasts results in reduced proliferation and the failure of refractory wounds to respond to treatment has therefore been proposed. However, in the chronic wounds of aged patients the precise relationship between the observed alteration in cellular responses with aging and replicative senescence remains to be determined. Using assays to assess cellular proliferation, senescence-associated staining beta-galactosidase, telomere length, and extracellular matrix reorganizational ability, chronic wound fibroblasts demonstrated no evidence of senescence. Furthermore, analysis of in vitro senesced fibroblasts demonstrated cellular responses that were distinct and, in many cases, diametrically opposed from those exhibited by chronic wound fibroblasts. Forced expression of telomerase within senescent fibroblasts reversed the senescent cellular phenotype, inhibiting extracellular matrix reorganizational ability, attachment, and matrix metalloproteinase production and thus produced cells with impaired key wound healing properties. It would appear therefore that the distinct phenotype of chronic wound fibroblasts is not simply due to the aging process, mediated through replicative senescence, but instead reflects disease-specific cellular alterations of the fibroblasts themselves.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry Medicine Systems Immunity Research Institute (SIURI)
Uncontrolled Keywords:	Cellular senescence; Chronic leg wounds; hTERT; Telomeres; Senescence; Immortalization; Telomerase
Publisher:	Elsevier
ISSN:	1090-2422
Last Modified:	06 Nov 2024 22:25
URI:	https://orca.cardiff.ac.uk/id/eprint/439

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