Intestinal crypts have great capacity for repair and regeneration after intestinal stem cell (ISC) injury. Here, we define the cellular remodeling process resulting from ISC niche interruption by transient Notch pathway inhibition in adult mice. Although ISCs were retained, lineage tracing demonstrated a marked reduction in ISC function after Notch disruption. Surprisingly, Notch ligand-expressing Paneth cells were rapidly lost by apoptotic cell death. The ISC-Paneth cell changes were followed by a regenerative response, characterized by expansion of cells expressing Notch ligands Dll1 and Dll4, enhanced Notch signaling, and a proliferative surge. Lineage tracing and organoid studies showed that Dll1-expressing cells were activated to function as multipotential progenitors, generating both absorptive and secretory cells and replenishing the vacant Paneth cell pool. Our analysis uncovered a dynamic, multicellular remodeling response to acute Notch inhibition to repair the niche and restore homeostasis. Notably, this crypt regenerative response did not require ISC loss.

肠隐窝在肠干细胞（ISC）损伤后具有很强的修复和再生能力。在这里，我们定义了成年小鼠中由瞬时 Notch 通路抑制引起的 ISC 生态位中断导致的细胞重塑过程。尽管保留了 ISC，但谱系追踪显示 Notch 中断后 ISC 功能显着降低。令人惊讶的是，表达Notch 配体的Paneth 细胞因凋亡细胞死亡而迅速丢失。ISC-Paneth 细胞变化之后是再生反应，其特征是表达 Notch 配体Dll1和Dll4的细胞扩增、Notch 信号增强和增殖激增。谱系追踪和类器官研究表明，DLL1表达细胞被激活以作为多能祖细胞发挥作用，产生吸收和分泌细胞并补充空缺的潘氏细胞池。我们的分析揭示了对急性 Notch 抑制的动态多细胞重塑反应，以修复生态位和恢复体内平衡。值得注意的是，这种隐窝再生反应不需要 ISC 损失。