Regenerative Hair Pigmentation via Skin Organoids: Adaptive Patterning Mediated by Collagen VI and Semaphorin 3C

Abstract The color patterns of mammalian fur are determined by melanocytes' ability to respond to and adapt to microenvironmental cues. However, these patterns can be lost following injury or under pathological conditions, and the underlying biological mechanisms remain poorly understood. In this study, reconstituted hair‐bearing skin is generated using skin organoids derived from dissociated epidermal cells, dermal cells, and melanocyte progenitors. The reconstituted skin exhibited pigmented hair patterns. By investigating the molecular cues involved in re‐establishing pigment patterns, it is demonstrated that this process is regulated through a two‐step mechanism. First, during skin organoid culture, signaling from dermal fibroblasts to melanocytes via the COL6A3‐CD44 pathway promotes the early maintenance of organotypic melanocytes. Subsequently, during hair follicle morphogenesis after skin organoid transplantation, signaling from the bulge to melanocytes via the SEMA3C‐NRP1 pathway regulates microtubule stability. This regulation guides melanocytes to migrate to their bulge stem cell niche, thereby enhancing hair pigmentation by promoting the adaptive patterning of melanocytes within the hair follicle. The study reveals two novel signaling mechanisms that shape melanocyte adaptive patterning and highlight the hair follicle as a regulatory hub for melanocyte physiological behaviors. These findings may inspire new clinical strategies for preventing hair greying.