{
  "abstract": "Aims: Fibroblasts are mesenchymal cells in the healthy vascular adventitia. In atherosclerosis, single-cell sequencing datasets suggest fibroblasts are abundant in plaques. However, their identity, origin, and fate during plaque progression remain unclear, which we aim to unravel here.\n\nMethods and results: To robustly define fibroblast identity, origin, and fate, we employed meta-analyses of 54 single-cell RNA sequencing libraries, including murine smooth muscle cell (Myh11) and endothelial cell (EC) (Cdh5) lineage reporter mice with and without atherosclerosis; human control and atherosclerotic arteries; and murine adventitia and atherosclerotic plaques processed separately from low-density lipoprotein (LDL) receptor knockout (Ldlr−/−) mice. These meta-analyses showed that murine and human plaque fibroblast identity was robustly defined by Pdgfra, Pi16, Cygb, and Serpinf1 mRNA. Ninety-five percent of plaque fibroblasts do not derive from the Myh11 lineage, while no Cdh5-lineage-positive cells were present in the fibroblast cluster. We identified five murine arterial fibroblast subsets in atherosclerotic murine aorta: progenitor fibroblasts, matrix fibroblasts, inflammatory fibroblasts, an EC-like fibroblast subset, detected in both adventitia and plaques, and Col5a3+ fibroblasts, unique to the adventitia. We next studied fibroblast identity, origin, and fate using pseudotime analysis and Pdgfra-CreERT2/tdTomato lineage reporter mice (Pdgfra Lin+). Healthy Pdgfra Lin+ reporter mice showed predominant adventitial tdTomato expression, and infrequent medial and intimal Pdgfra Lin+ cells co-expressing MYH11 and PECAM1, respectively. The Pdgfra Lin+ plaque area increased with diet duration. Pdgfra Lin+ cells largely maintain fibroblast identity in the plaque, while <10% co-express SMC markers (MYH11, SM22α), or contribute to ACTA2+ cap cells. ECs gaining mesenchymal markers are transcriptionally distinct from Cdh5-lineage-negative fibroblasts gaining EC markers. Plaque-resident EC-like fibroblasts displayed a mesenchymal-to-endothelial transition transcriptome, which was induced in human primary fibroblasts in vitro by starvation, and dampened or reversed by IL1B, TGFB1, TGFB3, and oxidized LDL. Cross-species integration showed that all murine plaque fibroblasts were conserved in human atherosclerosis, with one additional subset partially resembling murine subsets, and three human-specific subsets. Importantly, human fibroblast subsets differentially correlated to human plaque traits, with EC-like fibroblasts correlating to plaque instability.\n\nConclusion: Our results indicate that 95% of plaque-residing fibroblasts are Myh11 Lin− Plaque fibroblasts have a dual origin, predominantly adventitial Pdgfra Lin+ progenitor fibroblasts, with a minor contribution from medial Pdgfra Lin+ Myh11+ SMCs. Most plaque fibroblasts maintain fibroblast identity. Murine plaque fibroblast subsets were conserved in human atherosclerosis. EC-like fibroblasts are linked to human plaque instability. Intervening in progenitor-to-specific fibroblast transitions could present a new avenue to promote plaque stability in atherosclerosis.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 28,
  "authors": [
    {
      "name": "Guanliang Li",
      "orcid": "0000-0001-7995-7419"
    },
    {
      "name": "Sebastiaan E J Asselberghs",
      "orcid": "0000-0002-8983-5359"
    },
    {
      "name": "Baixue Yu"
    },
    {
      "name": "Cong Feng"
    },
    {
      "name": "Paul-Lennard Mendez",
      "orcid": "0000-0003-2025-7981"
    },
    {
      "name": "Dimitri Kasakovski",
      "orcid": "0000-0002-1426-132X"
    },
    {
      "name": "Pieter Goossens",
      "orcid": "0000-0002-7269-6372"
    },
    {
      "name": "Tia M Ackermans",
      "orcid": "0009-0001-4594-3972"
    },
    {
      "name": "Renée J H A Tillie",
      "orcid": "0000-0002-0648-4304"
    },
    {
      "name": "Marion J Gijbels"
    },
    {
      "name": "Lieve Temmerman",
      "orcid": "0000-0003-1102-0640"
    },
    {
      "name": "He Xu",
      "orcid": "0009-0009-2725-360X"
    },
    {
      "name": "Marjo M P C Donners",
      "orcid": "0000-0002-8519-8145"
    },
    {
      "name": "Dlzar A Kheder",
      "orcid": "0000-0002-6688-4537"
    },
    {
      "name": "Sidrah Maryam"
    },
    {
      "name": "Han Jin",
      "orcid": "0000-0002-0955-6289"
    },
    {
      "name": "Chenyi Xue",
      "orcid": "0000-0002-8829-7659"
    },
    {
      "name": "Sikander Hayat",
      "orcid": "0000-0001-5919-8371"
    },
    {
      "name": "Austin C Conklin",
      "orcid": "0000-0003-1710-5274"
    },
    {
      "name": "Casey E Romanoski",
      "orcid": "0000-0002-0149-225X"
    },
    {
      "name": "Mauro Giacca",
      "orcid": "0000-0003-2927-7225"
    },
    {
      "name": "Clint L Miller"
    },
    {
      "name": "Muredach P Reilly"
    },
    {
      "name": "Ming Chen",
      "orcid": "0000-0002-9677-1699"
    },
    {
      "name": "Rafael Kramann",
      "orcid": "0000-0003-4048-6351"
    },
    {
      "name": "Barend Mees",
      "orcid": "0000-0001-6545-5813"
    },
    {
      "name": "Andrew H Baker",
      "orcid": "0000-0003-1441-5576"
    },
    {
      "name": "Judith C Sluimer",
      "orcid": "0000-0002-0269-4582"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/47jjgr1j00rsm.bib",
  "cited_by": 0,
  "doi": "10.1093/cvr/cvag183",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13742058/",
  "id": "47jjgr1j00rsm",
  "issns": [
    "0008-6363",
    "1755-3245"
  ],
  "landing_url": "https://doi.org/10.1093/cvr/cvag183",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "AcademicSubjects/MED00200"
    ],
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      "heading",
      "Eurheartj/15"
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    [
      "heading",
      "Original Article"
    ],
    [
      "openalex",
      "2403|Atherosclerosis and Cardiovascular Diseases"
    ]
  ],
  "openalex": "W7212039971",
  "pdf_url": null,
  "pmcid": "PMC13742058",
  "pmid": "42713730",
  "published": "2026-09-09",
  "publisher": "Oxford University Press",
  "ris": "https://research.draconitic.com/paper/47jjgr1j00rsm.ris",
  "sources": [
    {
      "first_seen": "2026-11-10T12:22:58Z",
      "native_id": "PMC13742058",
      "source": "pmc",
      "url": "https://doi.org/10.1093/cvr/cvag183"
    }
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Atherosclerosis and Cardiovascular Diseases",
      "subfield": "immunology"
    }
  ],
  "title": "Atherosclerotic plaque fibroblasts derive from adventitial and medial Pdgfra-lineage-positive cells and predominantly maintain fibroblast identity",
  "title_text": "Atherosclerotic plaque fibroblasts derive from adventitial and medial Pdgfra-lineage-positive cells and predominantly maintain fibroblast identity",
  "type": "peer-reviewed",
  "updated_at": "2026-11-10T12:22:58Z",
  "url": "https://research.draconitic.com/paper/47jjgr1j00rsm",
  "venue": "Cardiovascular Research",
  "versions": []
}