Keloid fibroproliferative properties are dependent on stem cells modified by the HEDGEHOG-GLI1 pathway [EA1488]

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. In order to clarify the gene expression profile in keloids, we collected tissues from (1) central area of keloid, (2) marginal area of keloid, and (3) the normal skin surrounding the keloids, which were surgically resected. On the other hand, normal skin was collected from patients who underwent surgical treatment other than keloids and did not develop keloids, and was used as a normal control. Fibroblasts and stem cells derived from each were cultured and used as samples, and gene expression profile analysis was performed using Affymetrix microarray for comparison.