Hair

With alopecia affecting millions globally, recent advancements in the understanding of hair follicle biology have driven the development of novel therapies focused on hair regrowth. This review discusses two emerging therapeutic strategies: hair follicle neogenesis and the modulation of the Wnt/B-catenin signaling pathway. Hair follicle neogenesis, a frontier once considered impossible to achieve in adult humans, has recently gained traction due to advancements in stem cell biology and further understanding of the epithelial-mesenchymal interactions that are critical to hair follicle development. Such an approach shows significant potential for addressing conditions leading to hair loss, such as androgenetic and scarring alopecias. The Wnt/B-catenin signaling pathway, a critical intracellular pathway responsible for hair follicle cycles, has gained traction as a target for therapeutic interventions. Studies show that stimulating this pathway leads to hair follicle growth, while its inhibition prompts hair follicle regression. Investigations demonstrate clinical efficacy of small molecule inhibitors and peptides, such as PTD-DBM, which activates the Wnt/β-catenin pathway by interfering with CXXC5, a negative regulator that inhibits pathway activation. Such therapies show potential as more effective treatment options than existing solutions such as finasteride and minoxidil. Adjunctive therapies, such as low-level laser therapy, have also shown clinical efficacy, further highlighting how modulation of this pathway stimulates follicular regrowth. While these novel therapies require further research to validate their efficacy and to gain additional insight into their risk profile, it is clear that alopecia treatment is approaching a new frontier beyond traditional pharmacologic interviews, with regenerative medicine and pathway modulation paving the way forward.

C-low-threshold-mechanoreceptors (C-LTMR) were first discovered in the cat over 80 years ago and were subsequently documented in multiple mammalian species, including humans. Although their intimate association with hair follicles has been documented in mouse skin innervated by spinal ganglia, the functional anatomy in human skin is not known. The present study aimed to establish whether human C-LTMRs, also referred to as C-tactile (CT) afferents, have a functional association with hair follicles by determining their response to hair deflection using microneurography. Recordings from 15 consecutive CT afferents where the response to hair deflection was investigated showed that individual CT afferents respond to selective hair deflection. Mechanical hair plucking evoked after-discharge in CT afferents in the order of seconds following the stimulus. The results provide electrophysiological evidence that human CT afferents, similar to C-LTMRs in mice, have a functionally relevant anatomical relationship to hair follicles. KEY POINTS: In humans, recordings from 15 C-tactile afferents where the response to hair deflection was investigated, showed that individual C-tactile afferents respond to selective hair deflection. Mechanical hair plucking evoked after-discharge in C-tactile afferents in the order of seconds following the stimulus. The results provide electrophysiological evidence that human C-tactile afferents, similar to previously reported C-tactile afferents in mice, have a functionally relevant anatomical relationship to hair follicles.

Rationale: Hair loss affects millions globally, with limited effective treatments available and significant psychological impacts. Mesenchymal stem cells (MSCs) and MSC-derived exosomes hold therapeutic potential by modulating cellular communication, reducing inflammation, and supporting hair follicular regeneration. Rapamycin, a mechanistic target of rapamycin (mTOR) inhibitor, enhances MSC therapeutic potential by promoting the release of growth factors and signaling molecules. Thus, this study explores the benefit of priming effect of rapamycin on enhancing the function of MSC-derived exosomes to promote hair regrowth in a depilation-induced murine model. Methods: MSCs were primed with rapamycin, and exosomes were extracted from the MSC-conditioned media using ultrafiltration and poly (ethylene glycol) (PEG) precipitation. Dermal fibroblasts were treated with several doses of exosomes to evaluate the in vitro effect of rapamycin-primed MSC-derived exosomes (REXO). The depilated mice were administered exosomes via intradermal route and the hair regrowth was monitored for 15 days, followed by gene expression analysis and histological examination. Results: Dermal fibroblasts treated with REXO showed a higher proliferation rate and an increase in genes related to Wnt/β-catenin signaling, autophagy, and growth factors compared to non-primed MSC-derived exosomes (CEXO). In vivo REXO therapy via intradermal injection to the depilated areas in mice enhanced hair follicle development, hair density, and hair activation markers compared with the control and naive exosome treatments. Conclusion: REXO therapy effectively enhances hair regrowth thus this approach could offer a clinically effective therapy for hair loss treatment.

Hair follicle development is a complex, highly regulated process involving interactions between epithelial and mesenchymal cells. However, the specific molecular mechanisms and important biological processes of hair follicle development remain poorly understood. How the extracellular matrix is involved in the hair follicle formation from hair germs remains to be investigated. In this study, we applied spatially resolved proteomic mapping to investigate the process of hair follicle development in skin organoids at different stages: D55, D75, D90, D140, D150, and D170, which corresponds to that from hair germ formation to hair follicle aging. Our analysis identified dynamic changes in protein expression and active protein synthesis during hair follicle appearance. We observed stage-specific protein expression patterns, with hair germ and hair peg formation, enriched in proteins involved in RNA processing and lipid metabolism. Meanwhile, hair follicle initial and full maturation highlighted proteins related to keratinization and extracellular matrix organization. Notably, trend proteins involved in keratinization and neuron-neuron synaptic transmission were upregulated from hair germ formation to the hair follicle appearance. We also found that CSNK1A1 and SFN exhibit abnormal expression in the hair follicles of patients with cicatricial alopecia, which further proves the role of CSNK1A1 and SFN in the normal development of hair follicles. The results provide a comprehensive spatial proteomic map of hair follicle development and offer new insights into the biological process driving hair follicle formation and maturation. These findings may guide future therapeutic strategies for hair regeneration and the treatment of hair disorders.