Mechanical stimuli, such as stroking or pressing on the skin, activate mechanoreceptors transmitting information to the sensory nervous system and brain. It is well accepted that deflection of the hair fiber that occurs with a light breeze or touch directly activates the sensory neurons surrounding the hair follicle, facilitating transmission of mechanical information. Here, we hypothesized that hair follicle outer root sheath cells act as transducers of mechanical stimuli to sensory neurons surrounding the hair follicle. Using electrochemical analysis on human hair follicle preparations in vitro, we were able to show that outer root sheath cells release ATP and the neurotransmitters serotonin and histamine in response to mechanical stimulation. Using calcium imaging combined with pharmacology in a coculture of outer root sheath cells with sensory neurons, we found that the release of these three molecules from hair follicle cells leads to activation of sensory neurons.

Despite the substantial impact of skin scarring on patients and the healthcare system, there is a lack of strategies to prevent scar formation, let alone methods to remodel mature scars. Here, we took a unique approach inspired by how healthy hairbearing skin undergoes physiological remodelling during the regular cycling of hair follicles. In this pilot clinical study, we tested if hair follicles transplanted into human scars can facilitate tissue regeneration and actively remodel fibrotic tissue, similar to how they remodel the healthy skin. We collected full-thickness skin biopsies and compared the morphology and transcriptional signature of fibrotic tissue before and after transplantation. We found that hair follicle tranplantation induced an increase in the epidermal thickness, interdigitation of the epidermal-dermal junction, dermal cell density, and blood vessel density. Remodelling of collagen type I fibres reduced the total collagen fraction, the proportion of thick fibres, and their alignment. Consistent with these morphological changes, we found a shift in the cytokine milieu of scars with a long-lasting inhibition of pro-fibrotic factors TGFβ1, IL13, and IL-6. Our results show that anagen hair follicles can attenuate the fibrotic phenotype, providing new insights for developing regenerative approaches to remodel mature scars.