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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

18 Downloads (Pure)

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 language	English
Article number	113380
Number of pages	32
Journal	Cell Reports
Volume	42
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2023.113380
Publication status	Published - 28 Nov 2023

Keywords

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

Access to Document

10.1016/j.celrep.2023.113380Licence: CC BY-NC-ND

1-s2.0-S221112472301392X-mainFinal published version, 12.5 MBLicence: CC BY-NC-ND

Cite this

Mosquera, J. V., Auguste, G., Wong, D., Turner, A. W., Hodonsky, C. J., Alvarez-Yela, A. C., Song, Y., Cheng, Q., Lino Cardenas, C. L., Theofilatos, K., Bos, M., Kavousi, M., Peyser, P. A., Mayr, M., Kovacic, J. C., Björkegren, J. L. M., Malhotra, R., Stukenberg, P. T., Finn, A. V., ... Miller, C. L. (2023). Integrative single-cell meta-analysis reveals disease-relevant vascular cell states and markers in human atherosclerosis. Cell Reports, 42(11), Article 113380. https://doi.org/10.1016/j.celrep.2023.113380

@article{4bb94eb09905482790bd388bb2da059d,

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

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

author = "Mosquera, \{Jose Verdezoto\} and Ga{\"e}lle Auguste and Doris Wong and Turner, \{Adam W\} and Hodonsky, \{Chani J\} and Alvarez-Yela, \{Astrid Catalina\} and Yipei Song and Qi Cheng and \{Lino Cardenas\}, \{Christian L\} and Konstantinos Theofilatos and Maxime Bos and Maryam Kavousi and Peyser, \{Patricia A\} and Manuel Mayr and Kovacic, \{Jason C\} and Bj{\"o}rkegren, \{Johan L M\} and Rajeev Malhotra and Stukenberg, \{P Todd\} and Finn, \{Aloke V\} and \{van der Laan\}, \{Sander W\} and Chongzhi Zang and Sheffield, \{Nathan C\} and Miller, \{Clint L\}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = nov,

day = "28",

doi = "10.1016/j.celrep.2023.113380",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier",

number = "11",

}

Mosquera, JV, Auguste, G, Wong, D, Turner, AW, Hodonsky, CJ, Alvarez-Yela, AC, Song, Y, Cheng, Q, Lino Cardenas, CL, Theofilatos, K, Bos, M, Kavousi, M, Peyser, PA, Mayr, M, Kovacic, JC, Björkegren, JLM, Malhotra, R, Stukenberg, PT, Finn, AV, van der Laan, SW, Zang, C, Sheffield, NC & Miller, CL 2023, 'Integrative single-cell meta-analysis reveals disease-relevant vascular cell states and markers in human atherosclerosis', Cell Reports, vol. 42, no. 11, 113380. https://doi.org/10.1016/j.celrep.2023.113380

TY - JOUR

T1 - Integrative single-cell meta-analysis reveals disease-relevant vascular cell states and markers in human atherosclerosis

AU - Mosquera, Jose Verdezoto

AU - Auguste, Gaëlle

AU - Wong, Doris

AU - Turner, Adam W

AU - Hodonsky, Chani J

AU - Alvarez-Yela, Astrid Catalina

AU - Song, Yipei

AU - Cheng, Qi

AU - Lino Cardenas, Christian L

AU - Theofilatos, Konstantinos

AU - Bos, Maxime

AU - Kavousi, Maryam

AU - Peyser, Patricia A

AU - Mayr, Manuel

AU - Kovacic, Jason C

AU - Björkegren, Johan L M

AU - Malhotra, Rajeev

AU - Stukenberg, P Todd

AU - Finn, Aloke V

AU - van der Laan, Sander W

AU - Zang, Chongzhi

AU - Sheffield, Nathan C

AU - Miller, Clint L

PY - 2023/11/28

Y1 - 2023/11/28

N2 - 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.

AB - 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.

KW - Atherosclerosis/genetics

KW - Calcium-Binding Proteins/genetics

KW - Coronary Artery Disease/genetics

KW - Genome-Wide Association Study

KW - Humans

KW - Myocardial Infarction

KW - Myocytes, Smooth Muscle

KW - Plaque, Atherosclerotic

UR - https://www.scopus.com/pages/publications/85176251556

U2 - 10.1016/j.celrep.2023.113380

DO - 10.1016/j.celrep.2023.113380

M3 - Article

C2 - 37950869

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 11

M1 - 113380

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this