ArticlebioRxiv : the preprint server for biology2026
Transcriptomic, Specific Marker, and Pathway Analysis of Smooth Muscle Cell Foam Cells Relative to Macrophage Foam Cells in Human Atherosclerosis.
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19 authors.
Sima AllahverdianDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).
Yuancheng MaoDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).
Pinhao XiangDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).
Valentin BlanchardDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).
Aydin BölükDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).
Patrick A HartDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).
Paul ChengDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).ORCID 0000-0003-3429-2702
Daniel Y LiDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).ORCID 0000-0003-1015-6298
Matthew D WorssamDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).ORCID 0000-0003-4391-5377
Uma Thanigai ArasuDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).ORCID 0000-0002-5211-1007
Mari TaipaleDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).
Miika KiemaDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).
Johanna P LaakkonenDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).ORCID 0000-0002-8556-9727
Tiit ÖrdDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).
Minna U KaikkonenDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).ORCID 0000-0001-6294-0979
Clint L MillerDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).
Thomas QuertermousDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).ORCID 0000-0002-7645-9067
Teddy ChanDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).
Gordon A FrancisDepartment of Medicine, Centre for Heart Lung Innovation, Providence Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (S.A., Y.M., P.X., V.B., T.C., G.A.F.), Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA (P.A.H, C.L.M.), Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA (P.C., D.Y.L., M.W., T.Q.), A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (A.B., U.T.A., M.T., M.K., J.P.L., T. Ö., M.U.K.).ORCID 0000-0002-1691-3758
Funding
Stanford Center for Connecting DNA Variants to Function and PhenotypeUM1HG011972 · NHGRI · STANFORD UNIVERSITY · PI JESSE M ENGREITZ, THOMAS QUERTERMOUS · 2021 to 2026
$10.5MCausal variant association mechanisms in TCF21 binding coronary disease lociR01HL134817 · NHLBI · STANFORD UNIVERSITY · PI THOMAS QUERTERMOUS · 2017 to 2026
$6.2MMultimodal genetic regulatory architecture of coronary artery diseaseR01HL148239 · NHLBI · UNIVERSITY OF VIRGINIA · PI Clint L Miller · 2019 to 2026
$4.2MThe SMAD3 signaling network in coronary artery disease riskR01HL139478 · NHLBI · STANFORD UNIVERSITY · PI THOMAS QUERTERMOUS · 2018 to 2026
$3.7MMolecular Drivers of Atherosclerosis in DiabetesU01DK142283 · NIDDK · UNIVERSITY OF VIRGINIA · PI Mete Civelek, Clint L Miller · 2024 to 2026
$2.9MMolecular mechanisms of vascular calcification and their connection to coronary disease riskR01HL158525 · NHLBI · STANFORD UNIVERSITY · PI QUERTERMOUS, THOMAS · 2022 to 2025
$2.4MFunctional genomics investigation of pleiotropic vascular disease lociR01HL164577 · NHLBI · UNIVERSITY OF VIRGINIA · PI MILLER, CLINT L · 2022 to 2025
$2.3MGene regulatory networks controlling smooth muscle phenotype and vasculardisease riskR01HL171045 · NHLBI · STANFORD UNIVERSITY · PI THOMAS QUERTERMOUS · 2024 to 2026
$2.1MZEB1 Mediated Coronary Artery Disease Risk in Vascular Smooth MuscleK08HL177173 · NHLBI · STANFORD UNIVERSITY · PI DANIEL YUHANG LI · 2025 to 2026
$331kNHGRI NIH HHS UM1 HG011972NHLBI NIH HHS K08 HL177173NHLBI NIH HHS R01 HL134817NHLBI NIH HHS R01 HL139478NHLBI NIH HHS R01 HL148239NHLBI NIH HHS R01 HL158525NHLBI NIH HHS R01 HL164577NHLBI NIH HHS R01 HL171045NIDDK NIH HHS U01 DK142283
Abstract
backgroundSmooth muscle cells (SMCs) are reported to contribute the majority of cholesterol-overloaded foam cells in human and mouse atheromas. However, the transcriptome, specific markers, and biologic itinerary of SMC foam cells relative to macrophage foam cells have not been determined.
methodsTranscriptomic analysis by single cell RNA sequencing (scRNA-seq) was performed on fresh coronary segments from heart transplant recipients with early to intermediate stage atherosclerosis. The gene expression pattern of a putative cluster of SMC foam cells was compared to those of cultured SMCs loaded with either aggregated low density lipoprotein (agLDL) or cholesterol bound to methyl-β-cyclodextrin (Chol-MβCD). Candidate markers of SMC foam cells not expressed by macrophage foam cells were validated in ours and publicly available datasets, by spatial transcriptomics and by immunofluorescence microscopy of human atheromas. Pathway analysis was performed using Gene Set Enrichment Analysis Hallmark gene sets.
resultsSMC foam cells derived from fibromyocytes were tentatively identified using a panel of markers upregulated with in vitro cholesterol loading of SMCs. agLDL loading reproduced the same transcriptional profile, whereas Chol- MβCD did not reproduce any in vivo SMC state. Top genes highly represented in SMC foam cells included
conclusionsSMC foam cells, which are derived from fibromyocytes ("lipomyocytes"), exhibit unique markers and biologic programs that differ markedly from macrophage foam cells in atherosclerotic plaque development. Further understanding of the role of lipomyocytes and their expression of CFH and PAI-1 expression in plaque biology may offer novel therapeutic options to reduce ischemic cardiovascular disease.
Indexed as
atherosclerosiscoronary heart diseasefoam cellsmacrophagesSmooth muscle
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