GSE190938
Ablating Lgr5-expressing prostatic stromal cells activates the ERK-mediated mechanosensory signaling and disrupts prostate tissue homeostasis
The heterogeneity of the prostate stromal cells is widely appreciated but the functional implication remains incompletely understood. Using genetic lineage tracing and light-sheet imaging, we show that some fibroblast cells near the junction of 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. These changes are not mediated via endocrine or nervous regulation but can be phenocopied by physical disruption of prostatic lumen integrity. RNA-Seq analysis implies that ablating the Lgr5+ stromal cells activates a mechanosensory response, which is supported by increased prostate tissue stiffness and activation of the mitogen-activated protein kinase (MAPK). Suppressing MAPK overrides the increased epithelial proliferation. This study demonstrates that the Lgr5+ stromal cells regulate tissue homeostasis in a long-distance manner by maintaining anatomic integrity and implies that the cells near the transitional regions between organs likely control organ homeostasis by sustaining a balanced mechanoforce. Overall design: To understand the molecular changes induced by the ablation of the Lgr5+ stromal cells, we FACS-isolated the basal, luminal, and stromal cells from anterior prostates of DT-treated Lgr5-DTR-eGFP and control wild type mice and compared their gene expression profiles by RNA-seq.