Single-cell profiling of human plaques reveals cellular and molecular signatures of symptomatic atherosclerosis
- 1Institute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU Medizin, LMU Munich, Munich, Germany
Abstract
Atherosclerotic plaque vulnerability drives ischemic cardiovascular events, yet the cellular and molecular signatures distinguishing symptomatic from asymptomatic human plaques remain poorly defined. Here, we compared 53 symptomatic and asymptomatic human carotid plaques using single-nucleus (snRNA-seq; 17 samples, 19,100 nuclei; AtherOMICS biobank) and single-cell RNA sequencing (scRNA-seq; 36 samples, 68,983 cells; four public datasets), analyzed independently and combined by meta-analysis. Across sequencing approaches, symptomatic plaques showed cell-state shifts toward later or terminal states in osteochondrogenic smooth muscle cells (SMCs) and CD4 T cells, as well as transcriptional changes toward inflammatory and epithelial-to-mesenchymal transition (EMT) in endothelial cells (ECs), T cells, and fibroblasts. Nuclear profiling uncovered a depletion of fibroblasts in symptomatic plaques, marked by downregulation of RGS5. Integrating these transcriptomic signatures with genome-wide association data for coronary, cerebrovascular, and peripheral atherosclerotic disease, we found that genetic risk was enriched primarily in vascular wall cells (SMCs, fibroblasts, ECs), rather than immune cell types. The analyses further nominated higher TWIST1 expression in ECs (colocalized with risk across four atherosclerotic phenotypes), lower GUCY1A1 expression in fibroblasts and macrophages, and higher MRAS expression in T cells as candidate driver mechanisms linking genetic risk to symptomatic plaque transition. These findings provide novel insights into cellular and molecular phenotypes associated with plaque vulnerability and identify potential driver mechanisms of symptomatic plaque transformation that could inform therapeutic development.
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BibTeX
@misc{ray2026singlecell,
title = {{Single-cell profiling of human plaques reveals cellular and molecular signatures of symptomatic atherosclerosis}},
author = {A. Ray and L. Zivkovic and L. Zhang and R. Batool and A. Marei and M. Dichgans and N. Tsilimparis and M. K. Georgakis},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.07.26367408},
url = {https://www.medrxiv.org/content/10.64898/2026.11.07.26367408v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Single-cell profiling of human plaques reveals cellular and molecular signatures of symptomatic atherosclerosis
AU - A. Ray
AU - L. Zivkovic
AU - L. Zhang
AU - R. Batool
AU - A. Marei
AU - M. Dichgans
AU - N. Tsilimparis
AU - M. K. Georgakis
PY - 2026
DA - 2026/11/07
PB - medRxiv
DO - 10.64898/2026.11.07.26367408
UR - https://www.medrxiv.org/content/10.64898/2026.11.07.26367408v1
AB - Atherosclerotic plaque vulnerability drives ischemic cardiovascular events, yet the cellular and molecular signatures distinguishing symptomatic from asymptomatic human plaques remain poorly defined. Here, we compared 53 symptomatic and asymptomatic human carotid plaques using single-nucleus (snRNA-seq; 17 samples, 19,100 nuclei; AtherOMICS biobank) and single-cell RNA sequencing (scRNA-seq; 36 samples, 68,983 cells; four public datasets), analyzed independently and combined by meta-analysis. Across sequencing approaches, symptomatic plaques showed cell-state shifts toward later or terminal states in osteochondrogenic smooth muscle cells (SMCs) and CD4 T cells, as well as transcriptional changes toward inflammatory and epithelial-to-mesenchymal transition (EMT) in endothelial cells (ECs), T cells, and fibroblasts. Nuclear profiling uncovered a depletion of fibroblasts in symptomatic plaques, marked by downregulation of RGS5. Integrating these transcriptomic signatures with genome-wide association data for coronary, cerebrovascular, and peripheral atherosclerotic disease, we found that genetic risk was enriched primarily in vascular wall cells (SMCs, fibroblasts, ECs), rather than immune cell types. The analyses further nominated higher TWIST1 expression in ECs (colocalized with risk across four atherosclerotic phenotypes), lower GUCY1A1 expression in fibroblasts and macrophages, and higher MRAS expression in T cells as candidate driver mechanisms linking genetic risk to symptomatic plaque transition. These findings provide novel insights into cellular and molecular phenotypes associated with plaque vulnerability and identify potential driver mechanisms of symptomatic plaque transformation that could inform therapeutic development.
ER -