Treatment of aged wound healing models with FGF2 and ABT-737 reduces the senescent cell population and increases...

Delayed tissue repair in the aged presents a major socio-economic and clinical problem. Age-associated delay in wound healing can be attributed to multiple factors, including an increased presence of senescent cells persisting in the wound. Although the transient presence of senescent cells is physiologic during the resolution phase of normal healing, increased senescent cell accumulation with age can negatively impact tissue repair. The objective of the study was to test interventional strategies that could mitigate the negative effect of senescent cell accumulation and possibly improve the age-associated delay in wound healing. We utilised a 3D in vitro senescent fibroblast populated collagen matrix (FPCM) to study cellular events associated with senescence and delayed healing. Senescent fibroblasts showed an increase in anti-apoptotic B-cell lymphoma 2 (BCL-2) family proteins. We hypothesized that reducing the senescent cell population and promoting non-senescent cell functionality would mitigate the negative effect of senescence and improve healing kinetics. BCL-2 inhibition and mitogen stimulation (FGF2) improved healing in the in vitro senescent models. These results were confirmed with an ex vivo human skin biopsy model. These data suggested that modulation of the senescent cell population with soluble factors improved the healing outcome in our in vitro and ex vivo healing models.