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.

中文翻译：

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Frizzled5 通过组织染色质可及性来控制小鼠肠上皮细胞的可塑性


肠上皮的稳态依赖于复杂但未充分了解的肠上皮可塑性机制。在这里，我们阐明了 Wnt 通路受体 Frizzled5 （Fzd5） 作为小鼠肠上皮细胞命运决定因素的关键作用。Lgr5 ⁺ 肠道干细胞 （ISC） 中 Fzd5 的缺失会损害它们的自我更新，而 Krt19 ⁺ 细胞中 Fzd5 的缺失会破坏谱系生成，而在任何一种情况下都不会影响隐窝的完整性。然而，跨上皮 Fzd5 的更广泛缺失会导致隐窝严重恶化。单细胞 RNA 测序 （scRNA-seq） 和单细胞 ATAC-seq （scATAC-seq） 的综合分析确定，Fzd5 控制染色质的可及性，主要在 ISC 和祖细胞中协调干细胞和谱系相关基因表达的调节。总之，我们的研究结果为 Fzd5 在控制肠上皮可塑性中的调节作用提供了见解。