Deng Lu, He Xi C, Chen Shiyuan, Zhang Ning, Deng Fengyan, Scott Allison, He Yanfeng, Tsuchiya Dai, Smith Sarah E, Epp Michael, Malloy Seth, Liu Fang, Hembree Mark, Mu Qinghui, Haug Jeffrey S, Malagola Ermanno, Hassan Huzaifa, Petentler Kaitlyn, Egidy Rhonda, Maddera Lucinda, Russell Jonathon, Wang Yan, Li Hua, Zhao Chongbei, Perera Anoja, Wang Timothy C, Kuo Calvin J, Li Linheng
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Dev Cell. 2025 Feb 3;60(3):352-363.e6. doi: 10.1016/j.devcel.2024.10.021. Epub 2024 Nov 22.
The homeostasis of the intestinal epithelium relies on intricate yet insufficiently understood mechanisms of intestinal epithelial plasticity. Here, we elucidate the pivotal role of Frizzled5 (Fzd5), a Wnt pathway receptor, as a determinant of murine intestinal epithelial cell fate. Deletion of Fzd5 in Lgr5 intestinal stem cells (ISCs) impairs their self-renewal, whereas its deletion in Krt19 cells disrupts lineage generation, without affecting crypt integrity in either case. However, a broader deletion of Fzd5 across the epithelium leads to substantial crypt deterioration. Integrated analysis of single-cell RNA sequencing (scRNA-seq) and single-cell ATAC-seq (scATAC-seq) identifies that Fzd5 governs chromatin accessibility, orchestrating the regulation of stem- and lineage-related gene expression mainly in ISCs and progenitor cells. In summary, our findings provide insights into the regulatory role of Fzd5 in governing intestinal epithelial plasticity.
肠道上皮的稳态依赖于肠道上皮可塑性的复杂但尚未完全理解的机制。在这里，我们阐明了卷曲蛋白5（Fzd5）（一种Wnt信号通路受体）作为小鼠肠道上皮细胞命运决定因素的关键作用。在Lgr5肠道干细胞（ISC）中缺失Fzd5会损害其自我更新能力，而在Krt19细胞中缺失Fzd5则会破坏谱系生成，两种情况下均不影响隐窝完整性。然而，在上皮细胞中广泛缺失Fzd5会导致隐窝严重退化。单细胞RNA测序（scRNA-seq）和单细胞ATAC测序（scATAC-seq）的综合分析表明，Fzd5控制染色质可及性，主要在ISC和祖细胞中协调对干细胞和谱系相关基因表达的调控。总之，我们的研究结果为Fzd5在控制肠道上皮可塑性中的调节作用提供了见解。
