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.