Medical Department, Division of Gastroenterology and Hepatology, Charité University Medicine, 13353, Berlin, Germany.
Department of Molecular Biology, Max Planck Institute for Infection Biology, 10117, Berlin, Germany.
Nat Commun. 2019 Sep 25;10(1):4368. doi: 10.1038/s41467-019-12349-5.
The colonic epithelial turnover is driven by crypt-base stem cells that express the R-spondin receptor Lgr5. Signals that regulate epithelial regeneration upon stem cell injury are largely unknown. Here, we explore the dynamics of Wnt signaling in the colon. We identify two populations of cells with active Wnt signaling: highly proliferative Lgr5/Axin2 cells, as well as secretory Lgr5/Axin2 cells. Upon Lgr5 cell depletion, these cells are recruited to contribute to crypt regeneration. Chemical injury induced by DSS leads to a loss of both Lgr5 cells and Axin2 cells and epithelial regeneration is driven by Axin2 cells, including differentiated Krt20 surface enterocytes. Regeneration requires stromal Rspo3, which is present at increased levels upon injury and reprograms Lgr5 but Lgr4 differentiated cells. In contrast, depletion of stromal Rspo3 impairs crypt regeneration, even upon mild injury. We demonstrate that Rspo3 is essential for epithelial repair via induction of Wnt signaling in differentiated cells.
结肠上皮细胞的更新由表达 R-spondin 受体 Lgr5 的隐窝基底部干细胞驱动。目前尚不清楚调节干细胞损伤后上皮再生的信号。在这里，我们研究了 Wnt 信号在结肠中的动态。我们鉴定出两种具有活跃 Wnt 信号的细胞群：高度增殖的 Lgr5/Axin2 细胞，以及分泌型 Lgr5/Axin2 细胞。在 Lgr5 细胞耗竭后，这些细胞被招募来参与隐窝再生。DSS 诱导的化学损伤导致 Lgr5 细胞和 Axin2 细胞的丢失，上皮再生由 Axin2 细胞驱动，包括分化的 Krt20 表面肠细胞。再生需要基质 Rspo3，损伤后其水平升高，并重新编程 Lgr5 但 Lgr4 分化细胞。相比之下，基质 Rspo3 的耗竭即使在轻度损伤时也会损害隐窝再生。我们证明，Rspo3 通过诱导分化细胞中的 Wnt 信号对于上皮修复是必需的。
