Ablating Lgr5-expressing prostatic stromal cells activates the ERK-mediated mechanosensory signaling and disrupts prostate tissue homeostasis

Functional implication of stromal heterogeneity in the prostate remains incompletely understood. Using lineage tracing and light-sheet imaging, we show that some fibroblast cells at the mouse proximal prostatic ducts and prostatic urethra highly express Lgr5. Genetic ablation of these anatomically restricted stromal cells, but not nonselective ablation of prostatic stromal cells, rapidly induces prostate epithelial turnover and dedifferentiation that are reversed following spontaneous restoration of the Lgr5⁺ stromal cells. RNA sequencing (RNA-seq) analysis indicates that ablating the Lgr5⁺ stromal cells activates a mechanosensory response. Ablating the Lgr5⁺ stromal cells impairs the control of prostatic ductal outlet, increases prostate tissue stiffness, and activates the mitogen-activated protein kinase (MAPK). Suppressing MAPK overrides the elevated epithelial proliferation. In summary, the Lgr5⁺ stromal cells regulate prostate tissue homeostasis and maintain its functional integrity in a long-distance manner. Our study implies that the cells at organ junctions most likely control organ homeostasis by sustaining a balanced mechanoforce.