Endothelial Reprogramming by Disturbed Flow Revealed by Single-Cell RNA and Chromatin Accessibility Study
Aitor Andueza,
Sandeep Kumar,
Juyoung Kim,
Dong-Won Kang,
Hope L. Mumme,
Julian I. Perez,
Nicolas Villa-Roel,
Hanjoong Jo
Affiliations
Aitor Andueza
Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Emory University, Atlanta, GA, USA
Sandeep Kumar
Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Emory University, Atlanta, GA, USA
Juyoung Kim
Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Emory University, Atlanta, GA, USA
Dong-Won Kang
Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Emory University, Atlanta, GA, USA
Hope L. Mumme
Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Emory University, Atlanta, GA, USA
Julian I. Perez
Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Emory University, Atlanta, GA, USA
Nicolas Villa-Roel
Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Emory University, Atlanta, GA, USA
Hanjoong Jo
Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Emory University, Atlanta, GA, USA; Corresponding author
Summary: Disturbed flow (d-flow) induces atherosclerosis by regulating gene expression in endothelial cells (ECs). For further mechanistic understanding, we carried out a single-cell RNA sequencing (scRNA-seq) and scATAC-seq study using endothelial-enriched single cells from the left- and right carotid artery exposed to d-flow (LCA) and stable-flow (s-flow in RCA) using the mouse partial carotid ligation (PCL) model. We find eight EC clusters along with immune cells, fibroblasts, and smooth muscle cells. Analyses of marker genes, pathways, and pseudotime reveal that ECs are highly heterogeneous and plastic. D-flow induces a dramatic transition of ECs from atheroprotective phenotypes to pro-inflammatory cells, mesenchymal (EndMT) cells, hematopoietic stem cells, endothelial stem/progenitor cells, and an unexpected immune cell-like (EndICLT) phenotypes. While confirming KLF4/KLF2 as an s-flow-sensitive transcription factor binding site, we also find those sensitive to d-flow (RELA, AP1, STAT1, and TEAD1). D-flow reprograms ECs from atheroprotective to proatherogenic phenotypes, including EndMT and potentially EndICLT.
