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
Affiliations
Jose Verdezoto Mosquera
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
Gaëlle Auguste
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
Doris Wong
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
Adam W. Turner
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
Chani J. Hodonsky
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
Astrid Catalina Alvarez-Yela
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA
Yipei Song
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA; Department of Computer Engineering, University of Virginia, Charlottesville, VA 22908, USA
Qi Cheng
CVPath Institute, Gaithersburg, MD 20878, USA
Christian L. Lino Cardenas
Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
Konstantinos Theofilatos
King’s British Heart Foundation Centre, King’s College London, London WC2R 2LS, UK
Maxime Bos
Department of Epidemiology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands
Maryam Kavousi
Department of Epidemiology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands
Patricia A. Peyser
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI 48019, USA
Manuel Mayr
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
Jason C. Kovacic
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
Johan L.M. Björkegren
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
Rajeev Malhotra
Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
P. Todd Stukenberg
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA
Aloke V. Finn
CVPath Institute, Gaithersburg, MD 20878, USA
Sander W. van der Laan
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands
Chongzhi Zang
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
Nathan C. Sheffield
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
Clint L. Miller
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; Corresponding author
Summary: 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.
