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<p>Carotid stenosis causes ischemic stroke in both sexes, but the clinical presentation and plaque characteristics differ. Here we run deep single-cell sequencing of 7,690 human carotid plaque cells from male and female patients. While we found no sex differences in major cell types, we identified a predominance of the osteogenic phenotype in smooth muscle cells, immunomodulating macrophages (MPs) and endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition in females. In males, we found smooth muscle cells with the chondrocytic phenotype, MPs involved in tissue remodeling and ECs with angiogenic activity. Sex-biased subcellular clusters were integrated with tissue-specific gene-regulatory networks (GRNs) from the Stockholm–Tartu Atherosclerosis Reverse Network Engineering Task study. We identified GRN195 involved in angiogenesis and T cell-mediated cytotoxicity in male ECs, while in females, we found GRN33 and GRN122 related to TREM2<sup>−</sup>/TREM1<sup>+</sup> MPs and endothelial-to-mesenchymal transition. The impact of GRN195 on EC proliferation in males was functionally validated, providing evidence for potential therapy targets for atherosclerosis that are sex specific.</p>

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Single-cell RNA sequencing reveals sex differences in the subcellular composition and associated gene-regulatory network activity of human carotid plaques

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月10日

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  • Katyayani Sukhavasi,
  • Giuseppe Mocci,
  • Lijiang Ma,
  • Chani J. Hodonsky,
  • Ernest Diez Benevante,
  • Lars Muhl,
  • Jianping Liu,
  • Sonja Gustafsson,
  • Byambajav Buyandelger,
  • Simon Koplev,
  • Urban Lendahl,
  • Michael Vanlandewijck,
  • Prosanta Singha,
  • Tiit Örd,
  • Mustafa Beter,
  • Ilakya Selvarajan,
  • Johanna P. Laakkonen,
  • Marika Väli,
  • Hester M. den Ruijter,
  • Mete Civelek,
  • Ke Hao,
  • Arno Ruusalepp,
  • Christer Betsholtz,
  • Heli Järve,
  • Jason C. Kovacic,
  • Clint L. Miller,
  • Casey Romanoski,
  • Minna U. Kaikkonen,
  • Johan L. M. Björkegren

摘要

Carotid stenosis causes ischemic stroke in both sexes, but the clinical presentation and plaque characteristics differ. Here we run deep single-cell sequencing of 7,690 human carotid plaque cells from male and female patients. While we found no sex differences in major cell types, we identified a predominance of the osteogenic phenotype in smooth muscle cells, immunomodulating macrophages (MPs) and endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition in females. In males, we found smooth muscle cells with the chondrocytic phenotype, MPs involved in tissue remodeling and ECs with angiogenic activity. Sex-biased subcellular clusters were integrated with tissue-specific gene-regulatory networks (GRNs) from the Stockholm–Tartu Atherosclerosis Reverse Network Engineering Task study. We identified GRN195 involved in angiogenesis and T cell-mediated cytotoxicity in male ECs, while in females, we found GRN33 and GRN122 related to TREM2−/TREM1+ MPs and endothelial-to-mesenchymal transition. The impact of GRN195 on EC proliferation in males was functionally validated, providing evidence for potential therapy targets for atherosclerosis that are sex specific.