The high turnover and regenerative capacity of the adult intestine relies on resident stem cells located at the bottom of the crypt. The enteric nervous system consists of an abundant network of enteric glial cells (EGCs) and neurons. Despite the close proximity of EGCs to stem cells, their in vivo role as a stem cell niche is still unclear. By analyzing the mouse and human intestinal mucosa transcriptomes at the single-cell level, we defined the regulation of EGC heterogeneity in homeostasis and chronic inflammatory bowel disease. Ablation of EGC subpopulations revealed that the repair potential of intestinal stem cells (ISCs) is regulated by a specific subset of glial fibrillary acidic protein (GFAP)⁺ EGCs. Mechanistically, injury induces expansion of GFAP⁺ EGCs, which express several WNT ligands to promote LGR5⁺ ISC self-renewal. Our work reveals the dynamically regulated heterogeneity of EGCs as a key part of the intestinal stem cell niche in regeneration and disease.

成人肠道的高周转和再生能力依赖于位于隐窝底部的常驻干细胞。肠神经系统由丰富的肠神经胶质细胞 (EGC) 和神经元网络组成。尽管 EGC 与干细胞非常接近，但它们在体内作为干细胞生态位的作用仍不清楚。通过在单细胞水平分析小鼠和人类肠黏膜转录组，我们定义了 EGC 异质性在稳态和慢性炎症性肠病中的调节。EGC 亚群的消融显示肠干细胞 (ISC) 的修复潜力受胶质纤维酸性蛋白 (GFAP) ⁺ EGC 的特定子集的调节。从机制上讲，损伤诱导 GFAP ⁺EGC，表达几种 WNT 配体以促进 LGR5 ⁺ ISC 自我更新。我们的工作揭示了 EGC 的动态调节异质性是再生和疾病中肠道干细胞生态位的关键部分。