Cholesteatoma-associated Wbroblasts modulate epithelial growth and diVerentiation through KGF/FGF7 secretion

© The Author(s) 2012. This article is published with open access at Springerlink.com Abstract The keratinocyte growth factor (KGF/FGF7), produced by stromal cells, is a key paracrine mediator of epithelial proliferation, diVerentiation and migration. Expression of the growth factor is increased in wound heal-ing and in hyperproliferative epithelial diseases, as a conse-quence of the activation of dermal Wbroblasts by the inXammatory microenvironment. The middle ear cholestea-toma, an aural epidermal pathology characterized by kerati-nocyte hyperproliferation and chronic inXammation, may represent a model condition to study the epithelial-mesen-chymal interactions. To develop an in vitro model for this disease, we isolated and characterized human primary cul-tures of Wbroblasts associated with the cholesteatoma lesion, analyzing their secretory behaviour and degree of diVerentiation or activation. Compared to the perilesional or control normal Wbroblasts, all cultures derived from cho-lesteatoma tissues were less proliferating and more diVer-entiated and their highly variable activated phenotype correlated with the secretion of KGF as well as of metallo-proteases 2 and 9. Culture supernatants collected from the cholesteatoma-associated Wbroblasts were able to increase the proliferation and diVerentiation of human keratinocytes assessed by the expression of Ki67 and keratin-1 markers. The single crucial contribution of the KGF released by Wbroblasts on the keratinocyte biological response was shown by the speciWc, although partial, block induced by inhibiting the KGF receptor or by immunoneutralizing the growth factor. Altogether, these results suggest that the activation of the stromal Wbroblasts present in the patholog-ical tissue, and the consequent increased secretion of KGF, play a crucial role in the deregulation of the epidermal pro-liferation and diVerentiation