Constructing and Using Cell Type Populations of the Human Reference Atlas

The human body contains [~]27-36 trillion cells of up to 10,000 cell types (CTs) within a volume of [~]62-120 liters (males) and 52-89 liters (females). The Human Reference Atlas (HRA) v2.3 provides a quantitative 3D framework of CTs across 73 reference organs and 1,283 3D anatomical structures (ASs). The HRA Cell Type Population (HRApop) effort has quantified CTs per AS using high-quality single-cell datasets processed through scalable, reproducible workflows and cell type annotation (CTann) tools. HRApop v1.0 includes reference CT populations for 73 ASs (112 when sex-specific) using 662 datasets spatially registered to 230 locations across 17 organs (31 when sex-specific). For 558 single-cell (sc-)transcriptomics datasets (11,042,750 cells), CTs and biomarker expressions were computed using Azimuth, CellTypist, and popV. To test generalizability, 104 sc-proteomics datasets (16,576,863 cells) were integrated. In total, HRApop includes 27,619,613 cells and serves as a healthy reference for researchers aiming to elucidate mechanisms underlying cellular interactions, FTU operations, and cellular and tissue level disease progression, which may facilitate advancements in basic discovery and lead to new therapeutic strategies.