Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction

• Published in: Nature communications Vol. 12; no. 1; p. 681
• Main Authors: Tombor, Lukas S, John, David, Glaser, Simone F, Luxán, Guillermo, Forte, Elvira, Furtado, Milena, Rosenthal, Nadia, Baumgarten, Nina, Schulz, Marcel H, Wittig, Janina, Rogg, Eva-Maria, Manavski, Yosif, Fischer, Ariane, Muhly-Reinholz, Marion, Klee, Kathrin, Looso, Mario, Selignow, Carmen, Acker, Till, Bibli, Sofia-Iris, Fleming, Ingrid, Patrick, Ralph, Harvey, Richard P, Abplanalp, Wesley T, Dimmeler, Stefanie
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 29.01.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adaptation; Animals; Cell activation; Cell adhesion & migration; Cell migration; Cell Movement - genetics; Cell Plasticity - genetics; Cell proliferation; Cell Proliferation - genetics; Cells, Cultured; Disease Models, Animal; Endothelial cells; Endothelial Cells - pathology; Endothelium - cytology; Endothelium - pathology; Epithelial-Mesenchymal Transition - genetics; Gene expression; Gene sequencing; Genes, Reporter - genetics; Heart attacks; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia; Inflammation; Injuries; Ischemia; Luminescent Proteins - genetics; Male; Mesenchyme; Metabolic rate; Metabolism; Mice; Mice, Transgenic; Myocardial infarction; Myocardial Infarction - pathology; Myocardium - cytology; Myocardium - pathology; Plastic properties; Plasticity; Ribonucleic acid; RNA; RNA-Seq; Signatures; Single-Cell Analysis; Tissues; Trajectory analysis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-20905-1

Endothelial cells play a critical role in the adaptation of tissues to injury. Tissue ischemia induced by infarction leads to profound changes in endothelial cell functions and can induce transition to a mesenchymal state. Here we explore the kinetics and individual cellular responses of endothelial cells after myocardial infarction by using single cell RNA sequencing. This study demonstrates a time dependent switch in endothelial cell proliferation and inflammation associated with transient changes in metabolic gene signatures. Trajectory analysis reveals that the majority of endothelial cells 3 to 7 days after myocardial infarction acquire a transient state, characterized by mesenchymal gene expression, which returns to baseline 14 days after injury. Lineage tracing, using the Cdh5-CreERT2;mT/mG mice followed by single cell RNA sequencing, confirms the transient mesenchymal transition and reveals additional hypoxic and inflammatory signatures of endothelial cells during early and late states after injury. These data suggest that endothelial cells undergo a transient mes-enchymal activation concomitant with a metabolic adaptation within the first days after myocardial infarction but do not acquire a long-term mesenchymal fate. This mesenchymal activation may facilitate endothelial cell migration and clonal expansion to regenerate the vascular network.