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 Laan; Chongzhi Zang; Nathan C Sheffield; Clint L Miller

doi:10.1016/j.celrep.2023.113380

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

Cell Rep. 2023 Nov 28;42(11):113380. doi: 10.1016/j.celrep.2023.113380. Epub 2023 Nov 10.

Authors

Jose Verdezoto Mosquera¹, Gaëlle Auguste², Doris Wong¹, Adam W Turner², Chani J Hodonsky², Astrid Catalina Alvarez-Yela³, Yipei Song⁴, Qi Cheng⁵, Christian L Lino Cardenas⁶, Konstantinos Theofilatos⁷, Maxime Bos⁸, Maryam Kavousi⁸, Patricia A Peyser⁹, Manuel Mayr¹⁰, Jason C Kovacic¹¹, Johan L M Björkegren¹², Rajeev Malhotra⁶, P Todd Stukenberg¹³, Aloke V Finn⁵, Sander W van der Laan¹⁴, Chongzhi Zang¹⁵, Nathan C Sheffield¹⁵, Clint L Miller¹⁶

Affiliations

¹ Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA; Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
² Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
³ Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
⁴ Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA; Department of Computer Engineering, University of Virginia, Charlottesville, VA 22908, USA.
⁵ CVPath Institute, Gaithersburg, MD 20878, USA.
⁶ Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
⁷ King's British Heart Foundation Centre, King's College London, London WC2R 2LS, UK.
⁸ Department of Epidemiology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
⁹ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI 48019, USA.
¹⁰ King's British Heart Foundation Centre, King's College London, London WC2R 2LS, UK; National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
¹¹ Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
¹² Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Karolinska Institutet, 141 52 Huddinge, Sweden.
¹³ Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
¹⁴ Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands.
¹⁵ Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA; Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA; Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA.
¹⁶ Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA; Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA; Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: clintm@virginia.edu.

PMID: 37950869
DOI: 10.1016/j.celrep.2023.113380

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.

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

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Atherosclerosis* / genetics
Calcium-Binding Proteins / genetics
Coronary Artery Disease* / genetics
Genome-Wide Association Study
Humans
Myocardial Infarction*
Myocytes, Smooth Muscle
Plaque, Atherosclerotic*

Substances

CRTAC1 protein, human
Calcium-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding