Distinct dermal fibroblasts direct mechano-chemical signaling to the epidermis during pregnancy

Dermal fibroblasts alter extracellular matrix (ECM) and tissue mechanics dynamically in wound healing and fibrosis, however, are understudied in healthy skin remodeling across life stages. Here, by conducting spatio-temporal transcriptomics, we identified Cdh4 ⁺ dermal fibroblast subpopulation that remodels ECM and converts mechano-to-chemical signals to promote epidermal stem cell proliferation in expanding abdominal skin of pregnant mice. Mechanistically, Cdh4 ⁺ fibroblasts produce a pregnancy-responsive matrisome, resulting in denser and stiffer dermal fibrils. These fibroblasts then sense the stiffened substrate and convert the mechanical input into a chemical output via the YAP1-TGFβ2 axis, leading to the proliferation of epidermal stem cells via TGFβ receptor in the expanding skin. Thus, Cdh4 ⁺ fibroblasts fine-tune the dermal mechanofield and act as a mechanical-to-chemical signal conversion hub in healthy skin expansion.