LB1026 Role of skin cellular senescence in chronic wound healing

Abstract

Wound healing is an essential physiological process to restore normal skin structure and function after injury. Cellular senescence, an irreversible cell cycle state in response to damaging stimuli, has emerged as a paradigm shift to disrupt the traditional concept of wound healing beyond the described inflammatory, proliferative, and remodeling phases. We hypothesized that skin senescent cells, particularly fibroblasts, play an inhibitory role in the wound healing process and contribute to delayed healing. We generated an acute wound versus chronic wound mouse model to compare cellular senescence expression and their senescence-associated secretory phenotype (SASP) including growth factors, cytokines, and extracellular matrix remodeling factors. To validate our model, we first examined wound closure, degree of inflammation, epidermal hyperplasia, and degree of dermal fibrosis among others. Then, we assessed SASP profile in normal skin, acute wound, and chronic wound. Our data demonstrate Mmp3 (matrix metalloproteinase 3), Mmp9, Mcp (membrane cofactor protein), TGF-β (transforming growth factor β) which are key SASP factors involving in delayed would healing, significantly increased in chronic wounds. RNA in situ hybridization indicated increased p16ink4a (Cdkn2a) in chronic wounds, which is an intrinsic mediator in transition to cellular senescence. Furthermore, senescence-associated beta galactosidase staining showed enhanced senescent cells in chronic wounds. Taken together, cellular senescence may play a inhibitory role in chronic wound healing, and senescent cells clearance through systematic or topical senolytic treatment, may present a novel therapeutic option in the treatment of chronic wound disorders, including diabetic ulcers.