Absence of premature senescence in Werner's syndrome keratinocytes

B. Ibrahim, Angela Sheerin, Katrin Jennert-Burston, Joe L.E. Bird, M.V. Massala, Matthew Illsley, S.Elizabeth James, Richard Faragher

Research output: Contribution to journalArticle

Abstract

Werner's syndrome (WS) is an autosomal recessive genetic disorder caused by loss of function mutation in wrn and is a useful model of premature in vivo ageing. Cellular senescence is a plausible causal mechanism of mammalian ageing and, at the cellular level, WS fibroblasts show premature senescence resulting from a combination of telomeric attrition and replication fork stalling. Over 90% of WS fibroblast cultures achieve <20 population doublings (PD) in vitro compared to wild type human fibroblast cultures. It has been proposed that some cell types, capable of proliferation, will fail to show a premature senescence phenotype in response to wrn mutations. To test this hypothesis, human dermal keratinocytes (derived from both WS and wild type patients) were cultured long term. WS Keratinocytes showed a replicative lifespan in excess of 100 population doublings but maintained functional growth arrest mechanisms based on p16 and p53. The karyotype of the cells was superficially normal and the cultures retained markers characteristic of keratinocyte holoclones (stem cells) including p63 expression and telomerase activity. Accordingly we conclude that, in contrast to WS fibroblasts, WS keratinocytes do not demonstrate slow growth rates or features of premature senescence. These findings suggest that the epidermis is among the tissue types that do not display symptoms of premature ageing caused by loss of function of wrn. This is in support that Werner's syndrome is a segmental progeroid syndrome.
Original languageEnglish
Pages (from-to)139-147
Number of pages9
JournalExperimental Gerontology
Volume83
DOIs
Publication statusPublished - 2 Aug 2016

Bibliographical note

© 2016 This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/.

Keywords

  • Werner's syndrome
  • Keratinocytes
  • Fibroblasts
  • Cellular senescence
  • p53
  • p63
  • Ageing

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  • Cite this

    Ibrahim, B., Sheerin, A., Jennert-Burston, K., Bird, J. L. E., Massala, M. V., Illsley, M., James, S. E., & Faragher, R. (2016). Absence of premature senescence in Werner's syndrome keratinocytes. Experimental Gerontology, 83, 139-147. https://doi.org/10.1016/j.exger.2016.07.017