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

CERUTI, JULIETA M; GUSTAVO J. LEIROS; KUSINSKY, AG; MARÍA EUGENIA BALAÑA

Munich

Congreso; 46th Annual Meeting of the European Society for Dermatological Research (ESDR); 2016

ESDR

In androgenetic alopecia, circulating androgens act on dermal papilla cells (DPC) and alterparacrine factors that influence hair epithelial cells leading to hair follicle (HF) miniaturization.We showed that androgens deregulate DPC-secreted factors involved in normal HFstem cell (HFSC) differentiation inhibiting the canonical Wnt signalling pathway reported asimportant for hair morphogenesis and for the maintenance of DPC inductive properties. Inthis work, we studied the effect of dihydrotestosterone (DHT) and culture conditions on Wntagonists/antagonists balance in DPC and evaluated the role of the Wnt antagonist DKK-1 indermal papilla-induced HFSC differentiation. To assess the effect that culture conditionscould 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 ofthe agonists Wnt 5a and Wnt 10b, and upregulated the expression of Dkk1. Notably, in basalconditions, a higher expression of Wnt agonists was observed in DPC-spheroids culturesystem. HFSC differentiation was evaluated in presence of media conditioned by DPC afterandrogen treatment and in presence of DKK-1. DKK-1 presence in DPC culture abrogatedthe inductive ability of its conditioned medium mimicking the androgen effect previouslyreported. Furthermore, DPC-conditioned medium supplemented with Dkk-1 lost this HFSCdifferentiationinductive ability failing in the Wnt-b catenin pathway activation, evidenced byfailure of accumulation of b catenin in the cytoplasm of these cells. We conclude that threedimensional-tissuearchitecture of DPC-spheroids appears to contribute in maintaining Wntpathway activation, and probably DPC inductive properties. DHT can alter the balance ofWnt agonist/antagonist in DPC, reducing its ability to induce HFSC differentiation to hairlineage. 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.