Spatially resolved multiomics of human meningeal development reveal lineage and disease dynamics

The meninges are increasingly recognized as key stromal and immune niches supporting cranial development. Here we constructed a paired single-nuclei RNA and Assay for Transposase-Accessible Chromatin atlas of human meningeal development from 6 to 21 postconception weeks across cranial regions. By integrating spatial transcriptomics, we resolved cell types across meningeal layers. Our multiomic atlas defines gene regulatory networks underlying blood–brain barrier endothelial identity during development. Within immune compartments, the data support a yolk sac origin for meningeal myeloid lineages, including perivascular macrophages primed for barrier immunity. We present two analytical tools: Nichefinder, for spatial label transfer and proximity analysis, and cell2home, for inferring chemotactic signalling. Using cell2home, we identify interactions potentially driving B cell migration from cranial marrow into prenatal meninges. We studied trisomy 21, and observed reduced fibroblast chemokine expression with enhanced JAK–STAT signalling. Together, this work provides a developmental atlas of the human meninges and defines cellular and regulatory programs shaping early barrier immunity.