Researchers at Mount Sinai have generated the first organ-wide spatial atlas of human skin, providing a high-resolution map of cellular organization across the body. The study, published in Nature Genetics, identifies coordinated networks of interacting cell types—termed “multicellular neighborhoods,” that collectively maintain skin function and immune defense.
By profiling more than 1.2 million cells across 15 anatomical sites from 22 donors, the team characterized 45 distinct cell types and revealed how their spatial arrangement varies across different regions of the body.
Mapping the architecture of healthy skin
The skin is a highly complex organ that serves as both a physical barrier and an active immune interface. While previous studies have cataloged individual skin cell types, how these cells are spatially organized and interact across the body has remained poorly understood.
Using spatial transcriptomics, the researchers mapped gene expression directly to precise cellular locations within the skin. This enabled a multi-scale view of tissue organization, from organ-wide patterns down to local cellular interactions.
The analysis revealed that skin is structured into 10 recurrent multicellular neighborhoods, each composed of distinct combinations of immune and structural cells. These neighborhoods vary in abundance depending on anatomical location, reflecting site-specific functional demands.
Multicellular neighborhoods coordinate function
Rather than acting in isolation, skin cell types form organized interaction hubs that coordinate biological processes such as immune surveillance, barrier maintenance, and tissue repair.
One key example identified in the study is a “perivascular neighborhood” located around blood vessels. This niche contains immune cells, including T cells and dendritic cells, alongside specialized fibroblasts that help position and organize immune responses.
Within this microenvironment, tumor necrosis factor (TNF) signaling emerged as a central regulator. While TNF is typically associated with inflammation, the study highlights its role in maintaining fibroblast function and supporting immune–stromal communication in healthy skin.
The authors note that this perivascular structure resembles lymphoid tissues in other organs and may represent a form of skin-associated lymphoid tissue specialized for local immune monitoring.
Implications for skin disease
Many skin diseases, including psoriasis and eczema, occur at specific anatomical sites, suggesting that regional cellular organization plays a role in disease susceptibility.
By comparing spatial patterns across body sites, the researchers observed that disruptions in multicellular neighborhoods, particularly the perivascular niche, are associated with disease-related tissue dysfunction.
These findings suggest that targeting the interactions within specific cellular neighborhoods, rather than individual cell types alone, could represent a more effective therapeutic strategy.
Enabling technologies and future directions
A central enabler of the study was spatial transcriptomics, which allows high-throughput gene expression profiling while preserving tissue architecture. This technology provided what the authors describe as a “Google Maps”–like view of human skin, enabling navigation from whole-organ structure down to molecular detail.
“We reasoned that we need to understand what healthy skin looks like in order to fully understand human skin diseases,” said corresponding author Andrew L. Ji, MD. “These neighborhoods can be thought of as the key building blocks of human skin.”
The atlas establishes a foundational reference for future research, including efforts in tissue engineering, regenerative medicine, and targeted therapy development. By defining how healthy skin is organized, it provides a framework for identifying how these systems break down in disease—and how they might be restored.
As spatial and multi-omics technologies continue to evolve, integrating additional data layers onto this atlas may further refine our understanding of skin biology and accelerate the development of precision dermatology approaches.
