Department of Medicine, The University of Chicago, Chicago, IL 60637, USA; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA; Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
Dev Cell. 2023 Nov 6;58(21):2309-2325.e7. doi: 10.1016/j.devcel.2023.08.011. Epub 2023 Aug 30.
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.
慢性结肠损伤和炎症会导致高风险的“场癌变”，其中损伤相关的突变会促进干细胞适应性和逐渐的克隆扩增。然而，一些结肠炎相关突变场的长期稳定性可能暗示了其他起源。在这里，对急性小鼠结肠炎的研究揭示了在正常伤口愈合过程中大量中性克隆扩增的间歇性机制。通过三维（3D）成像、定量命运图谱和单细胞转录组学，我们发现上皮伤口修复始于对再生结构约束的丧失，形成包含上皮细胞的融合迷宫状通道，这些上皮细胞被重新编程为非增殖性的可塑性状态。随后出现一小部分但具有高度增殖能力的上皮创始祖细胞（FPC），并经历广泛的细胞分裂，从而实现类似流体的谱系混合和在结肠表面的扩散。隐窝芽生恢复了腺体组织，印迹了克隆扩增的模式。在可塑性的关键窗口期内，FPC 的出现和功能代表了具有癌前病变意义的再生靶标。
