Hair follicle (HF) cyclical growth is ruled by interactions between dermal papilla cells (DPC) and epidermal HF stem cells (HFSC). In androgenetic alopecia (AGA) androgens deregulate these interactions impairing HFSC differentiation. BMPs and WNTs maintain hair-inducing activity of DPC. We studied the role of BMPs on HFSC differentiation process to follicular linage, induced by DPC, and on its inhibition by androgens. The activity of alkaline phosphatase, marker hair inductivity, decreased in DPC spheres treated with DHT, and it was restored by the addition of BMP2. HFSC hair-linage differentiation was induced by conditioned media from DPC spheres. Media conditioned in presence of DHT, impaired HFSC differentiation, however, when DPC spheres media were conditioned in presence of DHT and BMP-2, or BMP2 was added to media before use, HFSC differentiation was recovered, suggesting that BMPs can overcome the inhibitory effect of DHT on HFSC differentiation. This effect of BMP2 was reproduced in heterotypic spheres composed of DPC and HFSC. It is known that Wnt/ ß-catenin signaling activation is necessary for HFSC differentiation. To deepen in the mechanism by which BMPs could be exerting the pro- differentiating activity, we analyzed the ß-catenin nuclear translocation in HFSC. When BMP2 was added to DPC spheres conditioned media, ß-catenin translocation was favored in differentiating HFSC compared with conditioned media alone or with DHT, implicating a cross-talk between BMPs and WNT signaling pathway in HFSC. Moreover, we found lower expression of Dkk-1, a known WNT signaling inhibitor, in BMP-2 treated DPC spheres. Even if further studies are necessary to elucidate at which level the cross-interactions of BMP and WNT signaling may occur, BMPs contribute to DPC inductivity and HFSC differentiation. We conclude that BMPs are critical factors of the complex epithelial-mesenchymal interaction and their downregulation contribute to AGA development.

Cross-interactions of BMP and WNT signaling pathways attenuate androgen effect on HFSC differentiation