A single-cell spatial transcriptomic census of human skin anatomy

The skin is the largest human organ and a site of significant disease burden, yet its cellular and molecular organization across the body are largely undefined. Here, we construct a spatially-resolved single-cell atlas of 1.2 million cells from normal adult human skin to localize 45 cell types across 15 anatomic sites. We define principles of organ-wide cell composition, including axes of cell diversity and specialization, and distinguish site-enriched cell types. Each body site is comprised of 10 multicellular neighborhoods that define cell-cell communication. Notably, we identify a perivascular neighborhood enriched for immune-stromal crosstalk with features resembling a homeostatic immune niche similar to skin-associated lymphoid tissue. Finally, mapping these neighborhoods onto skin disease reveals pathogenic neighborhood disruptions, including pan-disease immune alterations in the perivascular neighborhood. We present a framework charting the skins multiscale spatial organization across a molecular to macroanatomic scale. This work advances our understanding of organ-wide skin cellular organization and communication, and its architectural disruption in disease. HIGHLIGHTSO_LIHuman skin MERFISH spatial atlas of 1.2 million cells from 114 samples and 22 donors C_LIO_LICellular diversity varies along a central to peripheral body site spatial axis C_LIO_LI10 multicellular neighborhoods define skin microanatomy and homeostatic interactions C_LIO_LIHuman skin diseases feature spatial and transcriptional neighborhood remodeling C_LI