Multi-modal refinement of the human heart atlas during the first gestational trimester

Congenital heart defects are collectively frequent and a significant burden for human health. Understanding the developmental origins of such anomalies in the first and longest-lived vital organ is key to improving diagnoses, prognoses and therapies. However, although the atlas of human cardiac cells before birth continues to benefit from increased sampling, equivalencies across different investigators’ datasets or with animal models remain tenuous. We have determined the individual transcriptomes of nearly fifty thousand human heart cells from three fetuses between post-conceptional weeks (pcw) 8-11, and enriched their initial identification with a spatial transcriptomics analysis of six slices from two stage-matched samples. Integrations across modalities, sex and time points both internally and with earlier atlases have revealed the existence of previously unidentified, transient contractile, conductive and stromal cell types and their likely lineage relationships during the first trimester. Further analyses at varying levels of spatiotemporal resolution enabled us to validate charactistics of these cardiac cells in dozens of other samples and across a wide range of cell population sizes and ages. This resource advances knowledge about cell-autonomous states and adds precision to the repertory of contextual influences, including tissular and positional, exerted by and on the diverse lineages of the developing human heart during a critical time window.