Fibroblasts: Chronically Bad But Not So Down In The Mouth
Cardiff University, Cardiff, United Kingdom.
BACKGROUND - Chronic non-healing wounds are a major health problem within our ageing society. Such wounds are characterized by persistent inflammation, failed re-epithelialisation, a lack of granulation tissue formation and they are exacerbated by high levels of bacterial infection. Despite some clinical advances, 10-20% of chronic wounds still do not heal and thus novel therapeutic approaches are required. Our investigations have focussed on whether age-related functional changes in dermal fibroblasts may contribute to this dysfunctional healing phenotype. METHODS & RESULTS - Microarray analysis of chronic wound fibroblasts (CWFs) and normal skin fibroblasts (NFs) demonstrated altered regulation of numerous genes including molecules involved in the protection against oxidative stress. CWFs proliferate more slowly than NFs and premature senescence of CWFs was confirmed by increased SA beta-Gal activity and their larger, polygonal morphology. Analysis of telomere lengths revealed that whilst senescence in some CWFs was telomere-dependent in others it was telomere-independent. This premature senescence significantly decreased their abilities to carry out key wound healing activities. This is however, in direct contrast to fibroblasts isolated from wounds that heal in a scarless manner (oral mucosal fibroblasts; OMFs) that demonstrate differential gene analysis, increased proliferation, lower levels of senescence (longer telomeres) and accelerated wound healing responses. From our microarray data we have now described a transcriptional signature for this ‘wound healing continuum’ which may assist in the therapeutic assessment/treatment of a patient’s wound. Our recent findings however, suggest it is the presence of a progenitor cell sub-population resident within the heterogeneous oral stromal population that is key to the preferential healing. Such oral mucosal lamina propria-progenitor cells (OMLP-PCs) can berapidly and clonally expanded in vitro,are neural crest-derived and are multipotent. Furthermore, they are potently immunosuppressive and have distinct antibacterial activities. Such activities may be delivered by a distinct population of OMLP-PC exosomes which are currently under investigation. CONCLUSIONS - We postulate that OMLP-PCs could be an efficacious cell-based therapy for the future amelioration of chronic wounds.
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