Lgr5+ intestinal stem cells (ISCs) are crucial for the intestinal epithelium renewal and regeneration after injury. However, the mechanism underlying the interplay between Wnt and BMP signaling in this process is not fully understood. Here we report that Bcl11b, which is downregulated by BMP signaling, enhances Wnt signaling to maintain Lgr5+ ISCs and thus promotes the regeneration of the intestinal epithelium upon injury. Loss of Bcl11b function leads to a significant decrease of Lgr5+ ISCs in both intestinal crypts and cultured organoids. Mechanistically, BMP suppresses the expression of Bcl11b, which can positively regulate Wnt target genes by inhibiting the function of the Nucleosome Remodeling and Deacetylase (NuRD) complex and facilitating the β-catenin-TCF4 interaction. Bcl11b can also promote intestinal epithelium repair after injuries elicited by both irradiation and DSS-induced inflammation. Furthermore, Bcl11b deletion prevents proliferation and tumorigenesis of colorectal cancer cells. Together, our findings suggest that BMP suppresses Wnt signaling via Bcl11b regulation, thus balancing homeostasis and regeneration in the intestinal epithelium.

中文翻译：

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BMP 通过 Bcl11b 调节的 NuRD 复合物抑制 Wnt 信号传导以维持肠道干细胞。


Lgr5+ 肠道干细胞 （ISC） 对于损伤后肠上皮细胞的更新和再生至关重要。然而，在此过程中 Wnt 和 BMP 信号传导相互作用的潜在机制尚不完全清楚。在这里，我们报道了被 BMP 信号下调的 Bcl11b 增强了 Wnt 信号以维持 Lgr5 + ISC，从而促进了损伤后肠上皮的再生。Bcl11b 功能的丧失导致肠隐窝和培养的类器官中 Lgr5+ ISCs 的显着降低。从机制上讲，BMP 抑制 Bcl11b 的表达，Bcl11b 可以通过抑制核小体重塑和脱乙酰酶 （NuRD） 复合物的功能并促进 β-catenin-TCF4 相互作用来正向调节 Wnt 靶基因。Bcl11b 还可以促进照射和 DSS 诱导的炎症引起的损伤后的肠上皮修复。此外，Bcl11b 缺失可防止结直肠癌细胞的增殖和肿瘤发生。总之，我们的研究结果表明，BMP 通过 Bcl11b 调节抑制 Wnt 信号传导，从而平衡肠上皮的稳态和再生。