Absence of premature senescence in Werner's syndrome keratinocytes

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 less than 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 amongst 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.

Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

“…The mesenchymal lineage and connective tissue (e.g., fibroblasts) are overall more severely affected, which might be attributed to the premature senescence phenotype. However, premature senescence in vivo has been challenged by recent findings using dermal fibroblasts from autopsied WS patients (Ibrahim et al, ; Tokita et al, ). From our study, although premature senescence of WS‐MSCs (compared with gene‐corrected MSCs) could be observed in late passages, HGF deficiency was observed when MSCs were immediately differentiated from mesoderm precursors.…”

Research on Werner Syndrome: Trends from Past to Present and Future Prospects

“…As another example, keratinocytes, which comprise the epidermal tissue of the skin, have been reported to evade premature telomere dysfunction caused by WRN helicase deficiency [ 79 ]. Unlike fibroblasts in the dermis, keratinocytes possess telomerase activity and thereby play an important role in skin regeneration [ 80 ].…”

Tissue engineering strategies to bioengineer the ageing skin phenotype in vitro

“…Other studies have suggested that epidermal stem cell function is retained throughout life, as the abundance and functional capacity of epidermal stem cells were similar between young and aged murine skin, with regard to telomere length and expression of senescent markers (Giangreco et al, 2008 ; Stern & Bickenbach, 2007 ). Similarly, keratinocytes derived from Werner syndrome patients do not show evidence of premature senescence when cultured in vitro (Ibrahim et al, 2016 ).…”