Repurposing DPP4-Inhibition to Improve Hair Follicle Activation and Regeneration

Skin-injury and several diseases elicit fibrosis and induce hair follicle (HF)-growth arrest and loss. Resulting alopecia and disfiguration represent a severe burden for patients both physically and psychologically. Reduction of pro-fibrotic factors such as DPP4 might be a strategy to tackle this issue. We demonstrate DPP4-overrepresentation in settings with HF-growth arrest (telogen), HF-loss and non-regenerative wound areas in mice skin and human scalp. Topical DPP4-inhibition (DPP4i) with FDA/EMA-approved Sitagliptin (Sit) on preclinical models of murine HF-activation/regeneration results in accelerated anagen-progress, while treatment of wounds with Sit results in reduced expression of fibrosis markers, increased induction of anagen around wounds, and HF-regeneration in the wound center. These effects are associated with higher expression of Wnt-target Lef1, known to be required for HF-anagen (HF-activation)/regeneration. Sit-treatment decreases pro-fibrotic signaling in the skin, induce a differentiation trajectory of HF-cells, and activate Wnt-targets related to HF-activation/growth but not those supporting fibrosis. Taken together, our study demonstrates a role for DPP4 in HF biology and shows how DPP4i, currently used as oral medication to treat diabetes, could be repurposed into a topical treatment agent to potentially reverse HF-loss in alopecia and after injury. Overall design: Intradermal injection of Sitagliptin or PBS (conrol), 48 h after processing of the skin for scRNAseq