Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
Department of Hepatology and Gastroenterology, Charité University Medicine, Berlin, Germany.
Nat Cell Biol. 2019 Jul;21(7):812-823. doi: 10.1038/s41556-019-0339-9. Epub 2019 Jun 24.
Wnt signalling stimulated by binding of R-spondin (Rspo) to Lgr-family members is crucial for gastrointestinal stem cell renewal. Infection of the stomach with Helicobacter pylori stimulates increased secretion of Rspo by myofibroblasts, leading to an increase in proliferation of Wnt-responsive Axin2Lgr5 stem cells in the isthmus of the gastric gland and finally gastric gland hyperplasia. Basal Lgr5 cells are also exposed to Rspo3, but their response remains unclear. Here, we demonstrate that-in contrast to its known mitogenic activity-Rspo3 induces differentiation of basal Lgr5 cells into secretory cells that express and secrete antimicrobial factors, such as intelectin-1, into the lumen. The depletion of Lgr5 cells or the knockout of Rspo3 in myofibroblasts leads to hypercolonization of the gastric glands with H. pylori, including the stem cell compartment. By contrast, systemic administration or overexpression of Rspo3 in the stroma clears H. pylori from the gastric glands. Thus, the Rspo3-Lgr5 axis simultaneously regulates both antimicrobial defence and mucosal regeneration.
Wnt 信号通路受 R 脊椎蛋白（Rspo）与 Lgr 家族成员结合的刺激，对胃肠道干细胞的更新至关重要。幽门螺杆菌感染刺激肌纤维母细胞分泌更多的 Rspo，导致胃腺峡部的 Wnt 反应性 Axin2Lgr5 干细胞增殖增加，最终导致胃腺增生。基底 Lgr5 细胞也会受到 Rspo3 的刺激，但它们的反应尚不清楚。在这里，我们证明与已知的有丝分裂活性相反，Rspo3 诱导基底 Lgr5 细胞分化为分泌细胞，这些细胞将抗菌因子（如 intelectin-1）表达并分泌到腔中。肌纤维母细胞中 Lgr5 细胞的耗竭或 Rspo3 的敲除会导致幽门螺杆菌在胃腺中的过度定植，包括干细胞区室。相比之下，基质中 Rspo3 的系统给药或过表达可清除胃腺中的幽门螺杆菌。因此，Rspo3-Lgr5 轴同时调节抗菌防御和黏膜再生。
