Editors' ChoiceCELL BIOLOGY

Single-cell transcriptomic architecture of endothelial cells

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Science Translational Medicine  07 Oct 2020:
Vol. 12, Issue 564, eabe8123
DOI: 10.1126/scitranslmed.abe8123


Single-cell transcriptomics reveals organ-specific identities and sex-specific differences of endothelial cells.

Endothelial cells (ECs) line all vascular beds and are essential regulators of oxygen and nutrient delivery, vasodilation, and immune trafficking. Dissecting the functional specialization of ECs is key to understanding organ homeostasis and advancing the development of new organ-specific drugs and drug delivery methods for a great variety of diseases.

Paik et al. performed an organisms-wide analysis of EC single-cell transcriptional signature from 12 organs obtained from the Tabula Muris murine dataset. The authors found that ECs from some organs, such as brain and liver, presented unique transcriptional identities, whereas in other tissues (e.g., adipose, heart, aorta) they overlapped. Signaling pathway analysis confirmed shared and organ-specific pathways. Interestingly, common pathways such as Wnt and mitogen-activated protein kinase (MAPK) were regulated by distinct genes in each organ. A ligand-receptor interaction analysis identified unique crosstalks between ECs and parenchymal cells in each organ, further indicating the tissue-specialization of ECs.

Unsupervised clustering across all organs revealed a remarkable heterogeneity of ECs comprising 13 clusters, which included lung-specific ECs with antigen-presenting functions, cells expressing lymphatic markers, and ECs involved in response to infections and in endothelial-to-mesenchymal transition. Subsets of ECs within tissues were sex-specific, particularly in the brain, heart, and lung. Lars2, a non–sex-linked gene coding for leucyl-tRNA synthase 2, was expressed robustly in ECs from male but not female mice, a pattern confirmed at the protein level. Analysis of human fetal ECs confirmed that tissue specificity of ECs was preserved during development and largely conserved across mice and humans. However, neither human progenitor induced pluripotent stem cell (iPSC)– nor human embryonic stem cell (ESC)–derived ECs expressed organ-specific transcriptional signatures, indicating intrinsic limitations in current translational disease modeling and cell-based therapy applications.

Paik et al.’s single-cell analysis across tissues identified new markers of organ-specific ECs, signaling pathways, and sex-specific differences that could help explain known sex disparities in cardiovascular and other diseases. The future access to the ongoing effort to build a comprehensive human cell atlas (i.e., Human Cell Atlas and the Human BioMolecular Atlas Program) will offer opportunities to validate these findings and identify new transcriptional differences with respect to age, sex, and vascular organization within organs.

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