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Spatial and single-cell RNA sequencing reveals the immune microenvironment of human ascending thoracic aortic
Ke Zhen1, Zhiyong Du2, Pengcheng Wang3,4
1Experimental Research Center, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
Background:
Ascending thoracic aortic aneurysm (ATAA) is a fatal vascular disease characterized by immune dysregulation. However, the cellular composition, spatial localization, and functional diversity of immune cells in the ATAA microenvironment remain poorly understood.
Objective:
To construct a high-resolution immune cell atlas of human ATAA and explore the immune-mediated vascular remodelling mechanisms associated with its progression.
Method:
We conduct high-throughput single-cell RNA sequencing (scRNA-seq) of aortic tissues from eight ATAA patients and nine controls, including six from the GEO database. In the ATAA group, CD45+ cell subpopulations are isolated, and the scRNA-seq results are integrated with Visium high-definition spatial transcriptomics analysis to achieve near-single-cell resolution cell localization through deconvolution. Advanced cell segmentation algorithms are applied to generate a high-resolution immune cell atlas of human ATAA.
Results:
A total of 187 163 high-quality immune cells are identified, encompassing eight major immune cell types. Immune cells are significantly enriched in ATAA tissues compared with the controls. CellChat analysis reveals strong immune cell interactions in ATAA, which may contribute to its occurrence and progression.
Conclusion:
This study presents the first high-resolution immune cell atlas of human ATAA, offering novel insights into its immune-mediated vascular remodelling mechanism.
Key Points:
What is currently known about this topic? ATAA is a vascular disease characterized by medial degeneration and chronic inflammation. Previous single-cell transcriptomic studies have revealed the cellular heterogeneity of the aortic wall and identified alterations in the populations of smooth muscle, fibroblasts and endothelial cells. However, the immune landscape of ATAA remains unclear. Recent single-cell and spatial analyses of aortic dissections and abdominal aortic aneurysms have revealed dynamic immune remodelling involving macrophage polarization, T-cell activation and cytokine-driven matrix degradation. Nevertheless, the spatial resolution of immune heterogeneity and cross-lineage signalling in human ATAA is poorly understood. What is the key research question? This study aimed to determine the cellular composition, spatial distribution and transcriptional reprogramming of immune cell populations in ATAA and to elucidate how the interactions among immune cells lead to inflammation and pathological remodelling of the aortic wall. What is new? Single-cell RNA sequencing combined with Visium HD spatial transcriptomics can comprehensively characterize the composition, gene expression profiles and spatial localizations of eight types of immune cells in the aortic tissues of the control and ATAA groups at the single-cell level. Targeting of the interferon, AP1, and NF-κB pathways is a novel strategy for treating ATAA. The interactions among immune cells have a synergistic effect during ATAA formation, jointly driving immune remodelling. How might this study influence clinical practice? Elucidation of the dynamic differentiation trajectories and gene expression signatures of distinct immune cell populations in normal and ATAA-affected aortas will enhance our understanding of the immunological mechanisms underlying aneurysm pathogenesis. This knowledge provides a foundation for developing targeted anti-inflammatory therapeutic strategies for ATAA.
