EGR1-P21 axis promotes a stromal senescence-like phenotype and impairs enteric neural crest cell migration in Hirschsprung disease

Core Tip: Hirschsprung disease (HSCR) has long been studied through the lens of cellautonomous defects in enteric neural crest cells, yet the molecular identity of non-cellautonomous contributors has remained undefined.Here, by integrating HSCR patient colonic specimens, primary mouse embryonic intestinal fibroblasts and human fibroblast models with coculture migration assays, CUT&RUN-qPCR and dualluciferase reporter validation, we identified a stromal early growth response 1-P21 axis as a candidate mechanism that reshapes the intestinal microenvironment to impair enteric neural crest cell migration.This work identifies fibroblast-driven senescence-like and aberrant extracellular matrix remodeling as candidate targets for microenvironment-directed intervention in HSCR.