Coordinated Hedgehog Signaling Induces De Novo Hair Follicles in Primed Epithelial Structures

Mammalian organ development is orchestrated by coordinated molecular signals from epithelial and mesenchymal cells. In the skin, such anatomically adjacent signals cooperate to induce hair follicles (HF). However, this process only occurs during embryonic development, and viable strategies to induce new HFs in adult skin are lacking. Here, we reveal that supra-physiological activation of Hedgehog signaling in both epithelial and adjacent stromal cells induces new HFs in adult mouse skin. Importantly, the cells from which the new HFs derived were lineage traced from their originating touch-dome structure, and demonstrated similar molecular characteristics to embryonic HF development. Therefore, reactivation of productive, embryonic HF programs in adult skin has been achieved. In stark contrast, Hh-pathway activation in either epithelial or stromal cells alone resulted in tumor formation and stromal cell condensation, respectively, without induction of new HFs. Altogether, we demonstrate that cell-type specific modulation of a single pathway was sufficient to induce development of complex epithelial structures in the adult body, an important discovery with widespread implications for regenerative medicine.