Single‐Cell RNA Sequencing Reveals the Temporal Diversity and Dynamics of Cardiac Immunity after Myocardial Infarction

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

Nature Communications ◽

10.1038/s41467-021-20905-1 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 2

Author(s):

Lukas S. Tombor ◽

David John ◽

Simone F. Glaser ◽

Guillermo Luxán ◽

Elvira Forte ◽

...

Keyword(s):

Myocardial Infarction ◽

Endothelial Cells ◽

Endothelial Cell ◽

Single Cell ◽

Rna Sequencing ◽

Endothelial Cell Migration ◽

Metabolic Adaptation ◽

Endothelial Cell Proliferation ◽

Mesenchymal Transition ◽

Single Cell Rna Sequencing

AbstractEndothelial 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.

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Single-cell RNA Sequencing Reveals the Temporal Diversity and Dynamics of Cardiac Immunity after Myocardial Infarction

10.1101/2021.07.19.452902 ◽

2021 ◽

Author(s):

Kaiyu Jin ◽

Shan Gao ◽

Penghui Yang ◽

Rongfang Guo ◽

Dan Li ◽

...

Keyword(s):

Myocardial Infarction ◽

Single Cell ◽

Rna Sequencing ◽

Immune Cell ◽

Inflammatory Factors ◽

Coronary Artery Ligation ◽

Sequencing Analysis ◽

Artery Ligation ◽

Single Cell Rna Sequencing ◽

Time Specific

Myocardial infarction (MI) is strongly associated with the temporal regulation of cardiac immunity. However, a variety of current clinical trials have failed because of the lack of post-MI immunomodulating/anti-inflammatory targets. We performed single-cell RNA sequencing analysis of cardiac Cd45+ immune cell at 0, 3, 7, and 14 days after injury in a mouse left anterior descending coronary artery ligation model. Major immune cell populations, distinct subsets, and dynamic changes were identified. Macrophages (Mϕ)/monocytes were most abundant, peaking at 3 days after infarction. Mϕ-5 and Mϕ-6 were the predominant infiltrated subsets at this time point, with strong expression of inflammatory factors. Further analysis demonstrated that suppressing these sets attenuated pathological MI progression by preventing subsequent leukocyte extravasation and adverse remodeling. We also detected abundant apoptotic neutrophils and a profibrotic macrophage subset on days 7 and 14 respectively. These results provide a basis for developing cell type- and time-specific interventions in MI.

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