Integrative single-cell meta-analysis reveals disease-relevant vascular cell states and markers in human atherosclerosis

Jose Verdezoto Mosquera, Gaëlle Auguste, Doris Wong, Adam W. Turner, Chani J. Hodonsky, Astrid Catalina Alvarez-Yela, Yipei Song, Qi Cheng, Christian L. Lino Cardenas, Konstantinos Theofilatos, Maxime Bos, Maryam Kavousi, Patricia A. Peyser, Manuel Mayr, Jason C. Kovacic, Johan L.M. Björkegren, Rajeev Malhotra, P. Todd Stukenberg, Aloke V. Finn, Sander W. van der LaanChongzhi Zang, Nathan C. Sheffield, Clint L. Miller

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Coronary artery disease (CAD) is characterized by atherosclerotic plaque formation in the arterial wall. CAD progression involves complex interactions and phenotypic plasticity among vascular and immune cell lineages. Single-cell RNA-seq (scRNA-seq) studies have highlighted lineage-specific transcriptomic signatures, but human cell phenotypes remain controversial. Here, we perform an integrated meta-analysis of 22 scRNA-seq libraries to generate a comprehensive map of human atherosclerosis with 118,578 cells. Besides characterizing granular cell-type diversity and communication, we leverage this atlas to provide insights into smooth muscle cell (SMC) modulation. We integrate genome-wide association study data and uncover a critical role for modulated SMC phenotypes in CAD, myocardial infarction, and coronary calcification. Finally, we identify fibromyocyte/fibrochondrogenic SMC markers (LTBP1 and CRTAC1) as proxies of atherosclerosis progression and validate these through omics and spatial imaging analyses. Altogether, we create a unified atlas of human atherosclerosis informing cell state-specific mechanistic and translational studies of cardiovascular diseases.

Original languageEnglish
Article number113380
JournalCell Reports
Volume42
Issue number11
DOIs
StatePublished - 28 Nov 2023

Keywords

  • CP: Genomics
  • atherosclerosis
  • coronary artery disease
  • genome-wide association studies
  • integration analyses
  • single cell RNA-seq
  • smooth muscle cells

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