Tissue-level division of labor is coordinated across organs through universal programs and context-specific...

Fibroblasts, macrophages, and endothelial cells are common to most mammalian tissues, where they support homeostasis, repair, and immune regulation. Yet, how they coordinate functions across tissue environments remains unclear. Here, we analyze single-cell RNA sequencing data from 16 human tissues by using Pareto optimality and identify 15 archetypes- specialized programs reflecting functional tradeoffs. These include universal archetypes shared across tissues and tissue-specific archetypes shaped by local context. We show that tissues span a continuous archetype-distribution axis from metabolically active to barrier organs, suggesting coordinated adaptation. Ligand-receptor enrichment mapping uncovers communication between specialized archetypes, with spatial transcriptomics analysis supporting a subset of predicted interactions. Applying this approach to mouse tissues identifies related archetype programs, revealing evolutionarily conserved tradeoffs. These findings provide insight into how supportive cell division of labor is coordinated in health and how its dysregulation contributes to disease.