LGR5-positive fibroblasts orchestrate skin mechanoadaptation through JAK1 modulation

Abstract

Mechanical adaptation is a fundamental yet poorly understood process in stromal tissue biology. Here, we identify a population of LGR5+ mechanically induced regulatory fibroblasts (LGR5+ MIRFs) in mouse and human dermis, whose induction requires a YAP/AP-1-dependent transcriptional program. LGR5+ MIRFs channel mechanical input toward adaptive tissue remodeling by coordinating extracellular matrix reorganization while restraining inflammation. Their ablation or fibroblast-specific deletion of Lgr5 converts adaptive stretching into pathological fibro-inflammation, while dermal Lgr5 overexpression enhances tissue extensibility. Mechanistically, we uncover a non-canonical LGR5-JAK1 interaction that suppresses JAK-STAT signaling, directly coupling mechanosensing to kinase pathway activity. Topical JAK1 inhibition recapitulates the pro-remodeling effects of LGR5+ MIRFs, suggesting a translatable therapeutic strategy for optimizing skin expansion, treating striae, and mitigating fibrotic disorders. Our work redefines LGR5 as a conserved stromal mechanoresponder and provides a new conceptual framework for understanding adaptive tissue plasticity under mechanical stress. Mechanical stress induces LGR5+ fibroblasts that promote adaptive tissue remodeling by limiting fibrosis through JAK1 modulation. The study reveals a conserved mechanism of adaptation to mechanical stress and suggests a strategy for regenerative therapy.