{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:09:28Z","timestamp":1788952168213,"version":"build-2803163510"},"reference-count":81,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Dutch Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ASPASIA","award":["015.013.064"],"award-info":[{"award-number":["015.013.064"]}]},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["2016T060"],"award-info":[{"award-number":["2016T060"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["101031418-FIB-AGE"],"award-info":[{"award-number":["101031418-FIB-AGE"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["202308440165"],"award-info":[{"award-number":["202308440165"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["202106100042"],"award-info":[{"award-number":["202106100042"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["202308440136"],"award-info":[{"award-number":["202308440136"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Single-Cell Data Insights"},{"DOI":"10.13039\/100014989","name":"Chan Zuckerberg Initiative","doi-asserted-by":"publisher","award":["DAF2022-249406"],"award-info":[{"award-number":["DAF2022-249406"]}],"id":[{"id":"10.13039\/100014989","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and results<\/jats:title>\n                    <jats:p>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\u2212\/\u2212) 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 &amp;lt;10% co-express SMC markers (MYH11, SM22\u03b1), 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our results indicate that 95% of plaque-residing fibroblasts are Myh11 Lin\u2212 Plaque fibroblasts have a dual origin, predominantly adventitial Pdgfra Lin+ progenitor fibroblasts, with a minor contribution from medial Pdgfra Lin+ \u00a0Myh11+ 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag183","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T11:36:48Z","timestamp":1787657808000},"source":"Crossref","is-referenced-by-count":0,"title":["Atherosclerotic plaque fibroblasts derive from adventitial and medial\n                    <i>Pdgfra<\/i>\n                    -lineage-positive cells and predominantly maintain fibroblast identity"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7995-7419","authenticated-orcid":false,"given":"Guanliang","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8983-5359","authenticated-orcid":false,"given":"Sebastiaan E J","family":"Asselberghs","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]},{"name":"Department of Vascular Surgery, CARIM, MUMC , Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baixue","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, College of Life Sciences, Zhejiang University , Hangzhou ,","place":["China"]},{"name":"Bioinformatics Center, The First Affiliated Hospital, Zhejiang University , Hangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2025-7981","authenticated-orcid":false,"given":"Paul-Lennard","family":"Mendez","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1426-132X","authenticated-orcid":false,"given":"Dimitri","family":"Kasakovski","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]},{"name":"Department of Nephrology and Hypertension, Rheumatology and Immunology (Medical Clinic II), Medical Faculty RWTH Aachen , Pauwelsstra\u00dfe 30, 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7269-6372","authenticated-orcid":false,"given":"Pieter","family":"Goossens","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4594-3972","authenticated-orcid":false,"given":"Tia M","family":"Ackermans","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0648-4304","authenticated-orcid":false,"given":"Ren\u00e9e J H A","family":"Tillie","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion J","family":"Gijbels","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]},{"name":"Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences: Atherosclerosis & Ischemic Syndrome, Amsterdam UMC Location University of Amsterdam , Amsterdam ,","place":["the Netherlands"]},{"name":"Amsterdam Infection and Immunity: Inflammatory Diseases, Amsterdam UMC Location University of Amsterdam , Amsterdam ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1102-0640","authenticated-orcid":false,"given":"Lieve","family":"Temmerman","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2725-360X","authenticated-orcid":false,"given":"He","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8519-8145","authenticated-orcid":false,"given":"Marjo M P C","family":"Donners","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6688-4537","authenticated-orcid":false,"given":"Dlzar A","family":"Kheder","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidrah","family":"Maryam","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, Rheumatology and Immunology (Medical Clinic II), Medical Faculty RWTH Aachen , Pauwelsstra\u00dfe 30, 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0955-6289","authenticated-orcid":false,"given":"Han","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]},{"name":"Central Laboratory, Tianjin Medical University General Hospital , Tianjin ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8829-7659","authenticated-orcid":false,"given":"Chenyi","family":"Xue","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, Irving Institute for Clinical and Translational Research, Columbia University , New York, NY ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5919-8371","authenticated-orcid":false,"given":"Sikander","family":"Hayat","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, Rheumatology and Immunology (Medical Clinic II), Medical Faculty RWTH Aachen , Pauwelsstra\u00dfe 30, 52074 Aachen ,","place":["Germany"]},{"name":"Center of Excellence in Nephrology, University Hospitals Aachen, Cologne, Dusseldorf , Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1710-5274","authenticated-orcid":false,"given":"Austin C","family":"Conklin","sequence":"additional","affiliation":[{"name":"STEM Division, Northwest College , Powell, Wyoming ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0149-225X","authenticated-orcid":false,"given":"Casey E","family":"Romanoski","sequence":"additional","affiliation":[{"name":"The Department of Cellular and Molecular Medicine, The University of Arizona , Tucson ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2927-7225","authenticated-orcid":false,"given":"Mauro","family":"Giacca","sequence":"additional","affiliation":[{"name":"Molecular Medicine, International Centre for Genetic Engineering and Biotechnology (ICGEB) , Trieste ,","place":["Italy"]},{"name":"King's College London, British Heart Foundation (BHF) Centre of Research Excellence , London ,","place":["UK"]},{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste , Trieste ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clint L","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, University of Virginia , Charlottesville, Virginia ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muredach P","family":"Reilly","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, Irving Institute for Clinical and Translational Research, Columbia University , New York, NY ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9677-1699","authenticated-orcid":false,"given":"Ming","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, College of Life Sciences, Zhejiang University , Hangzhou ,","place":["China"]},{"name":"Bioinformatics Center, The First Affiliated Hospital, Zhejiang University , Hangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4048-6351","authenticated-orcid":false,"given":"Rafael","family":"Kramann","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, Rheumatology and Immunology (Medical Clinic II), Medical Faculty RWTH Aachen , Pauwelsstra\u00dfe 30, 52074 Aachen ,","place":["Germany"]},{"name":"Center of Excellence in Nephrology, University Hospitals Aachen, Cologne, Dusseldorf , Aachen ,","place":["Germany"]},{"name":"Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center , Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6545-5813","authenticated-orcid":false,"given":"Barend","family":"Mees","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, CARIM, MUMC , Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1441-5576","authenticated-orcid":false,"given":"Andrew H","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]},{"name":"BHF Centre for Cardiovascular Science, Queen\u2019s Medical Research Institute, University of Edinburgh , 47 Little France Crescent, Edinburgh EH16 4TJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0269-4582","authenticated-orcid":false,"given":"Judith C","family":"Sluimer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC) , P. Debyelaan 25, 6229 HX Maastricht ,","place":["The Netherlands"]},{"name":"Department of Nephrology and Hypertension, Rheumatology and Immunology (Medical Clinic II), Medical Faculty RWTH Aachen , Pauwelsstra\u00dfe 30, 52074 Aachen ,","place":["Germany"]},{"name":"Center of Excellence in Nephrology, University Hospitals Aachen, Cologne, Dusseldorf , Aachen ,","place":["Germany"]},{"name":"BHF Centre for Cardiovascular Science, Queen\u2019s Medical Research Institute, University of Edinburgh , 47 Little France Crescent, Edinburgh EH16 4TJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"2026090905475853300_cvag183-B1","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1093\/eurheartj\/ehac686","article-title":"Translational opportunities of single-cell biology in atherosclerosis","volume":"44","author":"de Winther","year":"2022","journal-title":"Eur Heart 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