Multiomics Analysis of Human Heart Tissues
Summary
In the present investigation, researchers employed a fusion of single-cell and spatial transcriptomic methodologies to elucidate, with unprecedented granularity, eight distinct regions and 75 varied cellular states within the human heart, inclusive of previously unexplored cardiac conduction system cells. The thorough scrutiny of these conduction system cells unveiled their characteristic ion channels, G-protein coupled receptors (GPCRs), and intricate regulatory networks, as well as established a connection between the pacemaker phenotype and the FOXP2 gene, which has ties to the cerebral language center's development. The findings suggest that the sinoatrial node exhibits compartmentalization, with pacemaker cells, fibroblasts, and glial cells constituting the essential foundation for glutamatergic signal propagation.
Research Criteria
In this scholarly endeavor, the authors amalgamate single-cell and spatial transcriptomic information to uncover cellular microenvironments residing in eight distinct human heart regions, chiefly centering on the cardiac conduction system and its interplay with diverse cell types and determinants. Moreover, the manuscript presents an innovative computational instrument, dubbed drug2cell, devised to forecast the ramifications of pharmacological agents on particular cardiac cells by examining their gene expression signatures.
Fig.1 Experimental design. (Kanemaru, 2023)
Sample Type
Human heart tissues.
Result—Multimodal Profiling of the Human Heart
Researchers employed an array of sophisticated technologies to scrutinize eight anatomical regions in samples from 25 donors aged between 20 and 75, all of whom were devoid of any cardiac disease or arrhythmia. The study amalgamated previously published single-cell/nuclei RNA sequencing (sc/snRNA-seq) datasets with newly generated multiome data—consisting of paired single-nucleus RNA sequencing (snRNA-seq) and single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq)—and spatial transcriptomics data. Harnessing the power of computational methods such as Leiden clustering and cell2location, the researchers identified 12 broad cell types and 75 cell states, including elusive populations within the cardiac conduction system such as P cells and AV bundle cells. Furthermore, they mapped these cell states onto their expected histologically identified structures, affirming their identities. This rigorous, multi-pronged approach elucidates the cellular landscape of the heart and paves the way for deeper insights into cardiac function and disease.
Fig.2 Adult human heart multimodal profiling. (Kanemaru, 2023)
Result—Unbiased Cellular Niche Discovery
In seeking to decipher the cellular composition of intricate microanatomical structures within the adult human heart, researchers deployed spatial transcriptomics to map fine-grained cell states as defined by single-cell/nuclei RNA sequencing. Concurrently, expert structural annotation of histological images was undertaken. Within the histologically annotated sinoatrial node samples, an enrichment of pacemaker cells, fibroblasts, and glial cells expressing neuronal growth factors was discovered. Similarly, atrioventricular node samples revealed the presence of fibroblasts, glial cells, and tissue-resident macrophages, along with pacemaker cells or atrioventricular bundle cells. To identify cellular niches in an unbiased manner, non-negative matrix factorization was used to decompose discernible structures. This analysis revealed that the sinoatrial node is a compartmentalized structure with functionally important pacemaker cells embedded among activated fibroblasts and glial cells, surrounded by a peripheral region of immune and fibroblast populations. This nuanced understanding of the cellular landscape provides a basis for further exploration of cardiac function and pathology.
Fig.3 Cellular niches in the adult human heart have been identified. (Kanemaru, 2023)
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Reference
- Kanemaru, K.; et al. Spatially resolved multiomics of human cardiac niches. Nature. 2023.
