Mechanisms of Dermal Papilla Engulfment During Hair Follicle Morphogenesis

Abstract

The dermal papilla (DP) is the mesenchymal signaling center of the hair follicle, required for hair shaft production and cyclic regeneration throughout postnatal life. How the follicular epithelium physically encloses the DP during embryonic morphogenesis remains poorly understood, despite this enclosure being recapitulated at the onset of every adult hair cycle and its failure being implicated in hair loss disorders such as androgenetic alopecia. To investigate the cellular and mechanical basis of DP engulfment, I developed a continuous Engulfment Index to stage mouse follicles between E16.5 and E17.5 along the wrapping progression, and combined cell-cycle profiling, three-dimensional morphometry, live imaging, and integrin perturbation to dissect the process spatially and temporally. Cell-cycle analysis showed that proliferation is broadly distributed across the matrix compartment rather than concentrated at the advancing front. However, a polar coordinate framework revealed a two-compartment organization: Geminin-positive cells span the full matrix arc while Ki67-enriched cells are specifically concentrated at the engulfment front tips. This front-specific Ki67 enrichment co-localizes with progressive cell elongation and elevated MYH9 actomyosin contractility. Live imaging and fixed-tissue analysis further revealed that basement membrane components are compositionally heterogeneous around the engulfing follicle and undergo spatially patterned redistribution during active enclosure. Functional blockade of α6 integrin selectively disrupted front-specific cell elongation and reduced the number of DP-contacting cells without broadly perturbing follicle organization. These findings support a model where DP engulfment integrates distributed matrix proliferation with a stable, front-specific program of cell-shape change, actomyosin contractility, and integrin-dependent basement membrane engagement.