慢性结肠损伤和炎症对于发生野癌化的风险很高，其中与损伤相关的突变促进干细胞的适应能力和逐渐的克隆扩张。然而，一些与结肠炎相关的突变野的长期稳定性可能表明了其他的起源。本文通过对急性小鼠结肠炎的研究揭示了正常伤口愈合过程中的一个间断机制，即大规模中性克隆扩张。通过三维成像、定量命运映射和单细胞转录组学等方法，我们展示了上皮组织修复从结构约束的丧失开始，形成了融合的迷宫通道，其中包含对非增殖可塑状态进行了重新编程的上皮细胞。随后，一小部分高度增殖的上皮创始祖细胞（FPCs）出现并经历广泛的细胞分裂，实现了像流体一样的谱系混合，并在结肠表面扩散。密窝发芽恢复了腺体组织的结构，印记了克隆扩张的模式。FPCs的出现和功能在可塑性窗口内代表了再生靶向治疗的对象，对前癌变具有重要意义。© 2023作者。由Elsevier公司出版，版权所有。

Chronic colonic injury and inflammation pose high risks for field cancerization, wherein injury-associated mutations promote stem cell fitness and gradual clonal expansion. However, the long-term stability of some colitis-associated mutational fields could suggest alternate origins. Here, studies of acute murine colitis reveal a punctuated mechanism of massive, neutral clonal expansion during normal wound healing. Through three-dimensional (3D) imaging, quantitative fate mapping, and single-cell transcriptomics, we show that epithelial wound repair begins with the loss of structural constraints on regeneration, forming fused labyrinthine channels containing epithelial cells reprogrammed to a non-proliferative plastic state. A small but highly proliferative set of epithelial founder progenitor cells (FPCs) subsequently emerges and undergoes extensive cell division, enabling fluid-like lineage mixing and spreading across the colonic surface. Crypt budding restores the glandular organization, imprinting the pattern of clonal expansion. The emergence and functions of FPCs within a critical window of plasticity represent regenerative targets with implications for preneoplasia.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.