Hmmr⁺ Fibroblasts Facilitate Hair Regeneration by Biomechanical Sensing of Extracellular Matrix Viscoelasticity

How fibroblast heterogeneity orchestrates tissue regeneration by remodeling tissue mechanical properties that guide stem cell function is not well understood. Although fibroblasts are increasingly recognized as key regulators of tissue homeostasis, the specific subpopulations and molecular pathways through which they remodel the mechanical niche during hair follicle regeneration are not fully defined. Here, we identify that Hmmr⁺ fibroblasts located beneath the dermal papilla (DP) of the hair follicle promote hair follicle regeneration by secreting extracellular matrix (ECM) components to activate hair follicle stem cells. Single-cell RNA-sequencing and immunostaining mapped spatially distinct fibroblast subpopulations in the dermal microenvironment and showed that regional ECM viscoelastic remodeling occurs prior to hair regeneration and coincides precisely with the emergence of Hmmr⁺ fibroblasts. Functional studies in vivo and in skin organoids demonstrate that Hmmr⁺ fibroblasts act as mechanical sensors that engage DP cells via NCAM1-FGFR1 signaling to stimulate hair regeneration. We propose a tripartite biomechanical module comprising ECM viscoelastic remodeling (effector), Hmmr⁺ fibroblasts (sensor), and DP cells (executor) that cooperatively drives hair regeneration. Together, our work identifies a heterogeneous fibroblast-defined mechanical niche as a central regulator of tissue renewal, highlighting the role of fibroblast diversity in coordinating regeneration and advancing our understanding of the mechano-molecular basis of tissue repair.