Siegfried, L. G. | bioRxiv Science

bioRxiv2026

BMP6 coordinates dermal papilla and epithelial cell states for hair follicle engineering and regeneration

Human hair follicle engineering is hindered by the rapid loss of inductive competence in culture-expanded dermal papilla (DP) fibroblasts. Here we show that bone morphogenetic protein 6 (BMP6) maintains and restores DP-associated characteristics while promoting follicular epithelial differentiation by restricting keratinocyte (KC) proliferation and inducing hair follicle-associated marker expression. Human follicle transcriptomics further linked BMP activity to DP identity and follicular epithelial differentiation. Genetic mouse studies demonstrate that BMP6 in Sox2-positive DP cells contributes to normal anagen onset, progression, and maintenance. Gain- and loss-of-function studies in KC-DP organoids show that BMP6 promotes epithelial-mesenchymal organization and spatially patterned follicular structures. In vivo, topical BMP6 promotes anagen onset, whereas BMP6 overexpression restores the hair follicle-generating capacity of late-passage human DP fibroblasts. Together, these findings identify BMP6 as a compartment-dependent regulator that enhances human DP competence and promotes epithelial differentiation, supporting regenerative hair follicle formation and engineering with culture-expanded DP cells.

developmental biology↗

bioRxiv2025

Actin-modulated nuclear shape controls adaptive reprogramming in cancer-associated fibroblasts

Cancer-associated fibroblasts (CAFs) exhibit striking plasticity, enabling them to adapt to external cues such as therapeutic and mechanical stress in the tumor microenvironment (TME). Here, we uncover a shared mechanotransduction pathway through which both BRAF inhibition and matrix stiffness converge in nuclear remodeling to drive CAF activation. Mechanistically, BRAF inhibitors (BRAFis) accelerate RAS-dependent RAF homo and heterodimerization and ERK signaling, leading to GSK-3{beta} inactivation and Rho kinase (ROCK) activation. In parallel, stiff substrates engage integrin receptors to directly activate ROCK signaling. Activation of ROCK induces actin stress fiber assembly, generating mechanical forces that deform the nucleus. In both contexts, nuclear reshaping promotes {beta}-catenin translocation and actin polymerization through a feedback loop that continuously enforces CAF activation and promotes melanoma progression. Notably, pharmacological inhibition of ROCK activity blocks both BRAFi- and stiffness-induced nuclear remodeling and {beta}-catenin accumulation, identifying the ROCK-cytoskeleton-nucleus axis as a critical regulator of CAF adaptation and functionality. Collectively, these findings reveal a mechanically tuned nuclear signaling hub that integrates chemical and physical cues to promote stromal adaptation and suggest ROCK inhibition as a strategy to counteract therapy-induced fibroblast reprogramming and improve therapy response.

cancer biology↗