Decoding the Human Vascular System: A Comprehensive Multi-organ Single-cell Transcriptomic Study Reveals Vascular Cell Diversity

Background Overview

The human vascular system is a core component for sustaining life, comprising endothelial cells (ECs) and mural cells that span across all organ systems. Its functions extend beyond merely delivering blood and facilitating gas and nutrient exchange—it plays critical roles in maintaining tissue homeostasis, immune regulation, angiogenesis, and pathological processes such as hypertension, cancer, inflammatory diseases, and diabetes. Endothelial cells exhibit diverse functions and molecular specificities based on organ and vessel type, such as the barrier properties of the blood-brain barrier and the red blood cell filtration in the spleen. However, a systematic classification of molecular characteristics across organs and vessel types has not yet been fully explored.

Against this backdrop, this study embarked on a comprehensive investigation to uncover the tissue-specific and molecular diversity of vascular cells, aiming to answer key scientific questions: How do endothelial and mural cells exhibit specificity across different organs? What are the molecular regulations and signaling pathways involved? This research is not only foundational to biological studies but also holds potential for identifying novel targets and strategies for treating vascular-related diseases.

Research Source

This study was conducted by a collaborative team from Imperial College London and the University of Cambridge, with lead authors M. Noseda and S. Tataridas. The research was published in the December 2024 issue of Nature Medicine (Volume 30, Pages 3468–3481). The article, titled An Organotypic Atlas of Human Vascular Cells, is accessible at https://doi.org/10.1038/s41591-024-03376-x.

Research Process

Data Integration and Quality Control

The research team integrated single-cell transcriptomic data from 19 human organs and tissues, sourcing 166 samples from 67 donors. After rigorous quality control and data cleaning, the analysis included approximately 800,000 single cells. Data integration was performed using the Single-Cell Variational Inference (scVI) algorithm, with Unified Manifold Approximation and Projection (UMAP) used for visualization.

Through initial identification, vascular endothelial and mural cells were distinguished into separate subtypes, and further differentiated from other cell types such as fibroblasts, immune cells, and smooth muscle satellite cells. Key marker genes for endothelial cells included CDH5, VWF, and PECAM1, while mural cells were characterized by markers such as PDGFRB and ACTA2.

Classification and Characterization of Multi-Organ Vascular Cells

The study identified 42 vascular-related cell states, further categorized into different subtypes of arterial, venous, capillary, and lymphatic endothelial cells, as well as organ-specific endothelial cell types. Key findings and research workflows are detailed as follows:

1. Layered Features of Arterial Endothelial Cells: Arterial endothelial cells were subdivided into three states: those derived from large vessels such as the aorta and coronary arteries (aorta_coronary_ec), and two small-caliber arterial subpopulations (art_ec_1 and art_ec_2). The aorta_coronary_ec population exhibited enriched expression of Sulfatase-1 (SULF1) and extracellular matrix-related genes such as ELN and small leucine-rich proteoglycans (SLRPs), indicating structural adaptations to high-pressure environments.

Trajectory inference analysis revealed a gradual transition from large arteries to small arteries and capillary endothelial cells, with specific genes such as NEBL peaking along the transition. This suggests that while arterial endothelial cells share common features across organs, they also exhibit nuanced differences along the arterial axis.

1. Immune Activation Features of Venous Endothelial Cells: Venous endothelial cells were classified into four subpopulations. Among them, ven_ec_1 was broadly distributed across most organs, expressing immune-related genes such as ACKR1 and POSTN. Another subpopulation, ven_ec_2, enriched in immune adhesion molecules like ICAM4 and SELE, suggested a role in immune cell recruitment. Furthermore, brain- and lung-specific venous endothelial cells (brain_ven_ec and pul_ven_ec) demonstrated higher tissue-specific gene expression, such as SH3RF3 (associated with Alzheimer’s disease).

2. Organ-specific Distribution of Lymphatic Endothelial Cells: Lymphatic endothelial cells (LECs) were categorized into seven subpopulations. One subtype, lymphatic capillary endothelial cells (cap_lec), exhibited uniform molecular signatures across multiple organs, including the expression of TFF3, a marker linked to pre-metastatic activity. This finding offers potential as a biomarker for predicting cancer metastasis.

3. Hybrid Phenotype of Littoral Endothelial Cells in the Spleen: Splenic littoral endothelial cells exhibited a mixed venous-lymphatic phenotype, co-expressing venous (ACKR1) and lymphatic (PROX1) markers. These cells were associated with red blood cell phagocytosis, and transcription factor network predictions identified NR5A1 as a key regulator of splenic vasculature development.

4. Functional Specialization of Capillary Endothelial Cells: Capillary endothelial cells in the heart and skeletal muscle (myo_cap_ec) were enriched in fatty acid metabolism-related genes such as FABP4 and MEOX2, while brain-specific capillary cells (blood_brain_barrier_ec) exhibited blood-brain barrier-specific markers, including MFSD2A and SLC38A3.

Drug Target Prediction and Cell Signaling Pathway Interpretation

Using the Drug2Cell platform, the research predicted vascular drug targets, identifying proteins such as P-selectin (SEL) as potential targets across various endothelial subgroups. Furthermore, Notch and Wnt signaling pathways were highlighted as key mediators of endothelial–mural cell interactions, reflecting angiotypic and organ-specific functional roles.

Key Conclusions and Significance

This study significantly advances our understanding of the diversity and functional specialization of human vascular cells through an integrated multi-organ vascular cell atlas. The findings are critical not only to basic biological research but also for identifying therapeutic targets for vascular dysfunction-related diseases such as hypertension, cancer, inflammation, and metabolic disorders. Specifically, the research demonstrates the shared molecular characteristics across organs, delineates tissue-specific differentiation states, and identifies potential drug targets. The data also serve as a template for healthy vascular cell references in pathological research.

Research Highlights

1. Methodological Innovations: By integrating advanced scVI algorithms and leveraging hierarchical clustering alongside spatial transcriptomics validation, the study provides robust approaches for analyzing complex biological data.

2. Comprehensive Data Coverage: Spanning 19 organs and tissues and defining 42 vascular cell states, this work represents the most comprehensive human vascular cell atlas to date.

3. Applications and Future Directions: The drug target predictions offer practical guidance for future therapeutic development, providing a foundation for disease treatment and novel pharmacological interventions.

The research team has made the data and resources openly accessible at https://www.vascularcellatlas.org/, inviting broader applications and extensions by the scientific community.