Keloid fibroproliferative properties are dependent on stem cells modified by the HEDGEHOG-GLI1 pathway [EA1874]

Keloids are benign fibroproliferative skin tumors caused by aberrant wound healing, the etiology of which is unknown. Although keloids cause life inconveniences and cosmetic problems, the lack of animal models has yet to elucidate their pathogenesis or develop effective treatments. Here, we found that the characteristics of stem cells from keloid lesions and surrounding dermis differ from those of normal skin and that HEDGEHOG (HH) signal and its downstream transcription factor GLI1 were upregulated in keloid patient-derived stem cells. Inhibition of the HH-GLI1 pathway reduced the expression of genes involved in keloids and fibrosis-inducing cytokines, including osteopontin. Moreover, HH-signal inhibitor vismodegib reduced keloid reconstituted tumor size and the expression of keloid related genes in nude mouse, and the collagen bundle and the expression of cytokines characteristic for keloids in ex vivo culture of keloid tissues. These results implicate the HH-GLI1 pathway in keloid pathogenesis and suggest therapeutic target of keloids. 2×10^6 keloid fibroblasts from the marginal area (KMF) from 3 patients or normal fibroblasts from 2 donors were mixed with hydrogel, including synthesized extracellular matrix supplemented with recombinant human IL-6. The mixtures were immediately injected subcutaneously into the dorsal surface of 6- to 8-week-old male nude mice. KMF-transplanted mice were treated with vehicle or vismodegib by intraperitoneal injection once a day. Mice were killed three months after implantation. RNA was isolated from the transplant to perform qPCR analysis and microarray assay.