Dermal papilla cells (DPCs) play a pivotal role in the regulation of hair follicle (HF) growth, formation, and cycling, mainly through paracrine mechanisms. In the last decade, extracellular vesicles (EVs) have been recognized as a new paracrine mechanism that can modify the physiological state of recipient cells by transferring biological material. Herein, we investigated the effect of EVs isolated from stimulated human dermal fibroblasts (DFs) on DPC activation and HF growth. We found that these EVs (st-EVs) enhanced HF growth ex vivo. Comparative transcriptomic analysis on DPCs identified specific activation of the NDP gene, encoding the non-Wnt ligand Norrin. We found that Norrin was secreted by st-EVs-stimulated DPCs activating in a noncell autonomous manner β-catenin pathway in follicular keratinocytes (human HF keratinocyte [HHFK]) and hair growth ex vivo. Although Norrin-specific receptor Frizzled4 was barely detected in HHFK, we found its presence in DF-EVs. Accordingly, DF-EVs provided Frizzled4 to potentiate Norrin effects ex vivo. Our study identifies DF-EVs as efficient activators of DPCs and Norrin as a novel modulatory player in HF physiopathology. STEM CELLS 2019;37:1166-1175 SIGNIFICANCE STATEMENTDermal papilla cells (DPCs) control the growth and regeneration of hair follicles (HFs) via cellcell interactions and extracellular molecules. These data demonstrate that activated dermal fibroblasts (DFs) secrete specific extracellular vesicles (st-EVs) that enhance HF growth ex vivo. DPCs treated with st-EVs secrete Norrin, a non-Wnt ligand that activates the β-catenin pathway of recipient human hair follicular keratinocytes. DF-EVs contain Norrin-specific Frizzled4 receptor that is barely detected in human HF keratinocytes. Combinatory treatment of Norrin and DF-EVs is sufficient to recapitulate the stimulating effect ex vivo of st-EVs on HF growth. The study identifies Norrin as a novel modulatory player in HF physiopathology.

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