Temporal-specific single-cell atlas of human type A aortic dissection reveals immune cell dynamics and therapeutic targets

This study is led by Cardiovascular Health Team from the Department of Nutrition and Health, China Agricultural University. Luo and colleagues analyzed 64,371 single immune cells by scRNA-seq coupled with TCR tracking using STARTRAC to quantitatively delineate their distinct functions and dynamic relationships in the context of temporal-specific AD. They identified 7 myeloid and 9 T cell subsets in human ascending aorta. Functional inferring revealed that both myeloid and T cells from acute/subacute AD showed higher inflammatory and aortic degenerative remodeling responses than that from chronic AD. STARTRAC analyses of T cell clonalities demonstrated that CD8⁺ T_EFF exhibited high clonal expansion and was developmentally connected with CD8⁺ T_EM, especially in subacute AD. Further ligand-receptor interactome analyses pointed to immune cell-derived TNF ligands in regulating aortic cells in both acute and subacute AD. Expression profiling and interactome analyses delineate disease stage-specific connectivity among vascular and immune subpopulations and identify immune cell-derived TNF as a pro-dissection factor. Finally, administration of etanercept (a clinical TNF-α antagonist) impedes aortic degeneration and dissection, and improves survival in the BAPN-induced AD model, opening new avenues for rationally and precisely tailored anti-AD therapies.

Here, the study identified 7 myeloid populations and 9 T cell populations with distinct functional characteristics that reside in human ascending aorta. The elevation of myeloid- and T cell-specific inflammatory pathways suggests a pro-inflammatory phenotype in AD progression. Additionally, their trajectory analysis shows a possibly indirect state transition from monocyte through TNF⁺ macrophage and/or MERTK⁺ macrophage to SPP1⁺ macrophage, C1QA⁺TAM-like, and M remodeling. A strong enrichment of inflammatory pathways was observed in monocytes, whereas C1QA⁺ TAM-like specifically enriched complement activation, antigen processing and presentation, and phagocytotic pathways, and M remodeling specifically exhibited tissue remodeling-related pathways. They also found that the elevation of ECM and protease expression was most prominent in acute AD, suggesting a disease stage-specific preference of ECM destruction during aortic degeneration.

Aside from myeloid clusters, the focal accumulation and activation of T cells have also been reported in aortic dissection. Their study indicated that effector CD8⁺ T cells exhibited the strongest cytotoxicity in the subacute group, while in the acute group, they had the most prominent pro-inflammatory effects. A powerful tool for characterizing the expression of genes in individual T cells is TCR sequences composed of α- and β-chains, which play major roles in the selection and activation of T cells. The author’s datasets provided a full temporal-specific repertoire of T cells and their potential clonal expansion and transition based on TCR tracking. The study suggested that the CD8⁺ T_EFF cluster exhibited the highest proportions of clonal cells and transition, contributing to pro-inflammatory cytokines production. Notably, CD8⁺ T HSP are mostly distributed in the acute group, indicating that the strongest immune reaction is induced by CD8⁺ T HSP. This study is the first to analyze the heterogeneity and characteristics of T cells from the perspective of time specificity of AD, which is helpful to understand the contribution of T cell populations in different disease subtypes, and further provide strategies for drug treatment of AD.

In this study, Luo and colleagues systematically depicted interactions between immune cells and vascular cells, such as AD-sharing chemokine interaction, acute-specific cytokine interaction and subacute-specific TNF interaction. Previous studies showed an elevation of serum TNF-α in patients with AD and might be associated with AD development. However, the immuno-origin of TNF ligands and their effecter cells across temporal-specific AD are still lacking. Notably, the author’s immune-vascular interaction analysis suggested that members of the TNF family ligands are derived from immune cells and might be involved in the development of AD (specifically the acute and subacute) by regulating vascular cells. Therefore, this study revealed that immune–derived TNF might promote vascular cell dysfunction and aortic degeneration at disease stage-specific AD.

Luo et, al used etanercept, an anti-TNF antagonist that has been approved by the US FDA for the treatment of inflammatory diseases, to treat AD. Strikingly, this study indicated that etanercept mitigates the development of AD, which expands the clinical application of etanercept and provides strong evidence for its future potential clinical application in AD drug therapy.

Taken together, this study provides the first comprehensive temporal-specific single immune cell atlas of human ascending aortas, which greatly broadens our understanding of aortic immune cell identities and functional diversity. It also offers novel insights into the molecular and cellular pathways/targets underlying AD pathogenesis and temporal transition in humans, and identifies the anti-inflammatory drug TNF-α antibody etanercept as a potential pharmacotherapy for the treatment of human AD.

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Temporal-specific single-cell atlas of human type A aortic dissection reveals immune cell dynamics and therapeutic targets