Multiomic analysis reveals developmental dynamics of the human heart in health and disease

Developmental dynamics encompass both the specification of cell types and their spatial organisation into multicellular niches. Here we harness the power of single-cell and spatial multiomics to unravel embryonic and foetal cardiac tissue niches, which lead to the development of a new tool, TissueTypist. We infer developmental cell trajectories, including evidence for lineage relationships based on shared somatic mutations, within first- and second-trimester human hearts. We reveal that cardiac-resident macrophages likely originate from the yolk sac, forming heterogeneous subsets. CX3CR1+ macrophages with a microglia-like profile localise in the sinoatrial node, which may contribute to axon guidance for the innervating autonomic neurons. Foetal pacemaker cells exhibit distinct characteristics compared to their adult counterparts, including the expression of genes that are known to promote parasympathetic innervation. By comparing somatic mutation profiles of cardiomyocytes, we identify an early branching point where pacemaker cells diverge from working cardiomyocytes. We highlight the enhancer-mediated gene regulatory networks governing atrial and ventricular cardiomyocyte specification. The maturation of atrial cardiomyocytes into distinct left and right phenotypes, driven by transcription factors linked to atrial septal defect genes, underscores the significance of this process for healthy heart development. In the ventricle, cellular and transcriptional gradients along both pseudotime and the transmural axis provide a new molecular understanding of myocardial compaction. Finally, generating data from Trisomy 21 hearts and comparing this with the euploid atlas, we reveal a reduced abundance of specific cell types including compact cardiomyocytes. Overall, this extensive dataset and our precomputed models will form a valuable resource for the field. ### Competing Interest Statement S.A.T. is a scientific advisory board member of ForeSite Labs, Qiagen and Element Biosciences, and a co-founder and equity holder of TransitionBio and EnsoCell Therapeutics, and a part-time employee of GlaxoSmithKline. S.S. is a co-founder and equity holder of ABS Biotechnologies. The remaining authors declare no competing interests.