Androgen action and 3D culture conditions influence dermal papilla cells inductive properties: the role of Wnt agonists/antagonists balance

CERUTI JM; LEIRÓS GJ; KUSINSKY, AG; BALAÑA ME.

Munich

Congreso; 46th Annual ESDR Meeting; 2016

European Society for Dermatological Research

In androgenetic alopecia, circulating androgens act on dermal papilla cells (DPC) and alter paracrine factors that influence hair epithelial cells leading to hair follicle (HF) miniaturization. We showed that androgens deregulate DPC-secreted factors involved in normal HF stem cell (HFSC) differentiation inhibiting the canonical Wnt signalling pathway reported as important for hair morphogenesis and for the maintenance of DPC inductive properties.In this work, we studied the effect of dihydrotestosterone (DHT) and culture conditions on Wnt agonists/antagonists balance in DPC and evaluated the role of the Wnt antagonist DKK-1 in dermal papilla-induced HFSC differentiation.To assess the effect that culture conditions could have on androgen-driven signals, monolayer and spheroids DPC cultures were established. The presence of DHT in both types of DPC cultures downregulated the expression of the agonists Wnt 5a and Wnt 10b, and upregulated the expression of Dkk1. Notably, in basal conditions, a higher expression of Wnt agonists was observed in DPC-spheroids culture system.HFSC differentiation was evaluated in presence of media conditioned by DPC after androgen treatment and in presence of DKK-1. DKK-1 presence in DPC culture abrogated the inductive ability of its conditioned medium mimicking the androgen effect previously reported. Furthermore, DPC-conditioned medium supplemented with Dkk-1 lost this HFSC-differentiation inductive ability failing in the Wnt-β catenin pathway activation, evidenced by failure of accumulation of β catenin in the cytoplasm of these cells.We conclude that three-dimensional-tissue architecture of DPC-spheroids appears to contribute in maintaining Wnt pathway activation, and probably DPC inductive properties.DHT can alter the balance of Wnt agonist/antagonist in DPC, reducing its ability to induce HFSC differentiation to hair lineage. The paracrine action of DKK-1 would be enough to abrogate HFSC differentiation, suggesting that DHT-inducible DKK-1 is involved in DHT-driven balding.