Dasatinib Attenuates Fibrosis in Keloids by Decreasing Senescent Cell Burden

Keloids are skin tumours caused by aberrant growth of dermal fibroblasts. Cellular senescence contributes to aging and various pathological conditions, including cancer, atherosclerosis, and fibrotic diseases. However, the effects of cellular senescence and senolytic drugs on keloids remain largely unknown. This study investigated senescent fibroblasts in keloids and assessed the effects of dasatinib on these cells. Tissues acquired from keloid removal surgery were analysed for senescence-associated β-galactosidase-positive cells, p16 expression, and the effects of dasatinib treatment on keloids. Keloid tissue was xenotransplanted into mice, and the effect of intralesional dasatinib injection on keloid growth was observed. The results showed that the numbers of β-galactosidase-positive and p16-expressing cells were higher in the keloids compared with in the controls. Dasatinib induced selective clearance of senescent cells and decreased procollagen expression in cultured keloid fibroblasts. In this xenotransplant keloid mouse model, intralesional injection of dasatinib reduced gross keloid tissue weight and the expression of both procollagen and p16. In addition, dasatinib-treated keloid fibroblasts conditioned medium reduced procollagen and p16 expression in cultured keloid fibroblasts. In conclusion, these results suggest that an increased number of senescent fibroblasts may play an important role in the pathogenesis of keloids. Therefore, dasatinib could be an alternative treatment for patients with keloids. SIGNIFICANCE Keloids are a fibroproliferative condition involving aberrant deposition of extracellular matrix including collagen because of dysregulated wound healing. Although surgical removal is possible, keloid recurrence is common, and other treatment modalities remain unsatisfactory. Senolysis is a therapeutic strategy to selectively eliminate senescent cells, consequently removing detrimental components of the senescence-associated secretory phenotype. This study showed that the anti-fibrotic effect of dasatinib in keloid fibroblast cultures and xenotransplant keloid tissue in mice involved the selective clearance of senescent cells and senescent-secreted secretome modulation. These results suggest a possible therapeutic application of senolytic treatment for keloids.