Immunoregulatory Endothelial Cells Interact With T Cells After Myocardial Infarction

作者：Lukas Tombor, Till Lautenschläger, Simone-Franziska Glaser, Ariane Fischer, Maximilian Merten, Susanne Hille, Oliver J. Müller, Christian Kupatt, Tarik Bozoglu, Christoph Kugler, Haider Sami, Manfred Ogris, Kathrin A. Stilz, Josefine Panthel, Marion Muhly-Reinholz, Lisa-Maria Kettenhausen, Lukas Zanders, Leonie Stein, Paul Kießling, Florian Sicklinger, Florian Leuschner, Bianca Schuhmacher, Mauro Siragusa, David Rodríguez Morales, David John, Haris Kujundzic, Minh-Thuy Katschke, Emmanouil G Solomonidis, Guillermo Luxán, Stephanie Hehlgans, Franz Rödel, Christoph Kuppe, Wesley Abplanalp, Sebastian Cremer, Stefanie Dimmeler · 发表于：Circulation Research · 年份：2025 · DOI：10.1161/circresaha.125.326145 · 被引用次数：12 · 研究领域：Cardiac Fibrosis and Remodeling、Atherosclerosis and Cardiovascular Diseases、Congenital heart defects research

BACKGROUND: Endothelial cells (ECs) play pivotal roles in maintaining cardiac blood supply and regulating inflammation by acting as gatekeepers for immune cell activity. This study unveils a novel immunomodulatory function of cardiac ECs following myocardial infarction. METHODS: We used single-cell RNA sequencing and spatial transcriptomics to identify EC states after acute myocardial infarction in mice. Subsequently, we mimicked the cytokine environment that was predicted to induce EC activation in cell culture studies and confirmed the results in an endothelial-specific deletion mouse model. RESULTS: Single-cell RNA sequencing analysis identified a transient myeloid CD45 + CD11b + Cdh5 + immunomodulatory EC phenotype (IMEC) emerging between days 1 and 3 after myocardial infarction. IMECs derived from Cdh5 + tissue resident cells as shown by bone marrow transplantation and lineage tracing experiment. Ligand-receptor interaction predictions indicated a cytokine-mediated activation of IMECs, which we validated through in vitro experiments in cultured ECs. Notably, while cytokine treatment with IL-1β and TGF-β (transforming growth factor β) induced mesenchymal gene expression, the addition of IFN-γ (interferon γ) facilitated the transition into the immunomodulatory phenotype. IMECs exhibited an upregulation of MHC-II (major histocompatibility complex class II) genes, along with the expression of RUNX1 (runt-related transcription factor-1) and proinflammatory cytokines, such as ...