Enteric glial cell heterogeneity regulates intestinal stem cell niches

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.