Mapping intestinal microenvironment heterogeneity in Hirschsprung’s disease by spatial transcriptomics: Role of THBS1 in macrophage polarization and neural stem cell regulation

The pathogenic role of the intestinal microenvironment on Hirschsprung's disease (HSCR) is increasingly recognized; however, the spatial expression patterns and underlying molecular mechanisms of the HSCR intestinal microenvironment remain unclear. In this study, we generated the first comprehensive spatial transcriptomic map of HSCR and revealed microenvironmental heterogeneity. Spatial transcriptomics revealed THBS1 as a consistently down-regulated gene in HSCR aganglionic segments. In vitro experiments using THP-1 and SH-SY5Y cells showed that THBS1 promoted M2-like polarization and interacted with SDC1. Furthermore, THBS1-overexpressing macrophages enhanced the proliferation and migration of SH-SY5Y cells in co-culture. These findings suggest a potential role for THBS1 in modulating macrophage-neural interactions in the HSCR microenvironment, though further validation in primary cells is needed.