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.前列腺间质细胞的异质性已得到广泛认知，但其功能意义仍未完全阐明。本研究通过遗传谱系示踪（genetic lineage tracing）与光片显微镜成像（light-sheet imaging）技术，发现小鼠近端前列腺导管与前列腺尿道连接区域附近的部分成纤维细胞高表达Lgr5。对这些解剖学定位限定的间质细胞进行遗传消融，而非对前列腺间质细胞进行非选择性消融，会快速诱导前列腺上皮更新与去分化，且该表型可在Lgr5阳性间质细胞自发恢复后得到逆转。上述变化并非通过内分泌或神经调控介导，但可通过破坏前列腺管腔完整性的物理操作实现表型模拟。RNA测序（RNA-Seq）分析显示，消融Lgr5阳性间质细胞会激活机械感应应答，该结论得到了前列腺组织硬度升高以及丝裂原活化蛋白激酶（MAPK）激活的支持。抑制MAPK可逆转上皮增殖水平的升高。本研究证实，Lgr5阳性间质细胞可通过维持解剖结构完整性，以远距离调控方式维持组织稳态；同时表明，器官间过渡区域附近的细胞可能通过维持平衡机械力来调控器官稳态。