Mammalian wound healing is a complex, multi-step process that must be tightly regulated. Whereas synthesis of extracellular matrix is an essential step in wound healing, excessive matrix deposition can lead to the formation of fibrotic scars, resulting in compromised structure and function of the affected organ or tissue. Some of the deleterious consequences of fibrotic wound healing include liver cirrhosis, pulmonary fibrosis, and congestive heart failure. On the other hand, deficient matrix deposition can play a role in impaired wound healing leading to chronic non-healing wounds, a complication for which patients with diabetes are at particular risk. Our recent studies have revealed that in the course of normal cutaneous wound healing, myofibroblasts in the granulation tissue are driven into senescence by CCN1, a matricellular protein that is dynamically expressed at sites of wound repair. CCN1 induces cellular senescence through a novel integrin-mediated pathway, and activates the expression of an anti-fibrotic genetic program characteristic of senescent cells. Mutant knockin mice that express a senescence-defective CCN1 do not accumulate senescent cells and suffer exacerbated fibrosis in wounds. These results support the hypothesis that CCN1-dependent cellular senescence is a programmed wound healing response that controls fibrogenesis. However, this mechanism of fibrosis control may become deregulated under pathological conditions, leading to excessive senescent cell accumulation and contributing to the chronicity of non-healing wounds. We will investigate the role of CCN1-induced cellular senescence in cutaneous wound healing in three specific aims: Aim 1 dissects the molecular mechanism of CCN1-induced senescence;Aim 2 evaluates the role of cellular senescence in controlling fibrosis during wound healing;and Aim 3 elucidates the effects of senescent cells on chronic non-healing wounds. Together, these studies will advance our knowledge of how cellular senescence participates in fibrosis control and chronicity in wound healing. PUBLIC HEALTH RELEVANCE: Wound healing is a complex, multi-step process that must be tightly regulated. Excessive deposition of extracellular matrix often occurs in association with chronic injuries, and may result in fibrosis with serious consequences such as liver cirrhosis and pulmonary fibrosis. Impaired wound healing can also lead to chronic non-healing wounds, which may require amputations. This proposal seeks to understand the role of cellular senescence in wound healing, which may underlie the pathologies of both fibrotic wound healing and chronic non-healing wounds. We anticipate that our results will prompt new therapeutic strategies that may reduce the morbidity and mortality associated with impaired wound healing.