Tissue-level division of labor is coordinated across organs through universal programs and context-specific adaptations
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Fibroblasts, macrophages, and endothelial cells are common to most mammalian tissues, where they support homeostasis, repair, and immune regulation. Yet how they coordinate their functions across diverse tissue environments remains unclear. Here, we analyze single-cell RNA sequencing data from 14 human tissues using Pareto optimality framework and identify 16 archetypes - specialized transcriptional programs representing functional tradeoffs. These include universal archetypes shared across tissues and tissue-specific archetypes shaped by local context. We find that tissues align along a continuous axis of archetype distributions, from metabolically active to barrier organs, reflecting coordinated functional adaptation. Using ligand-receptor enrichment mapping, we reveal task-specific crosstalk across cell types, suggesting that intercellular communication underlies supportive division of labor. Applying this analysis to mouse tissues, we find similar patterns, indicating evolutionary conserved tradeoffs. These findings provide a framework for understanding how division of labor is coordinated in health and how its dysregulation may contribute to disease.
