Human and murine fibroblast single-cell transcriptomics reveals fibroblast clusters are differentially affected by ageing and serum cholesterol.

Autor:	van Kuijk K; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands.; Institute of Experimental Medicine and Systems Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany., McCracken IR; BHF Centre for Cardiovascular Sciences (CVS), Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK., Tillie RJHA; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands., Asselberghs SEJ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands.; Department of Vascular Surgery, Maastricht University Medical Center, Maastricht, The Netherlands., Kheder DA; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands., Muitjens S; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands., Jin H; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands., Taylor RS; BHF Centre for Cardiovascular Sciences (CVS), Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK., Wichers Schreur R; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands., Kuppe C; Institute of Experimental Medicine and Systems Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.; Division of Nephrology and Clinical Immunology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany., Dobie R; Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK., Ramachandran P; Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam UMC, Amsterdam, The Netherlands., Gijbels MJ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands.; Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam UMC, Amsterdam, The Netherlands.; GROW, School for Oncology and Development Biology, Maastricht University, Maastricht, The Netherlands., Temmerman L; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands., Kirkwoord PM; Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK., Luyten J; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands.; Department of Vascular Surgery, Maastricht University Medical Center, Maastricht, The Netherlands., Li Y; Division of Cardiothoracic Surgery, Baylor College of Medicine, Houston, TX, USA.; Department of Cardiovascular Surgery, Texas Heart Institute, Houston, TX, USA., Noels H; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands., Goossens P; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands., Wilson-Kanamori JR; Division of Nephrology and Clinical Immunology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany., Schurgers LJ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands.; Institute of Experimental Medicine and Systems Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany., Shen YH; Division of Cardiothoracic Surgery, Baylor College of Medicine, Houston, TX, USA.; Department of Cardiovascular Surgery, Texas Heart Institute, Houston, TX, USA., Mees BME; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands.; Department of Vascular Surgery, Maastricht University Medical Center, Maastricht, The Netherlands., Biessen EAL; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands.; Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany., Henderson NC; Division of Nephrology and Clinical Immunology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK., Kramann R; Institute of Experimental Medicine and Systems Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.; Department of Vascular Surgery, Maastricht University Medical Center, Maastricht, The Netherlands., Baker AH; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands.; BHF Centre for Cardiovascular Sciences (CVS), Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK., Sluimer JC; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands.; BHF Centre for Cardiovascular Sciences (CVS), Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 Jul 04; Vol. 119 (7), pp. 1509-1523.
DOI:	10.1093/cvr/cvad016
Abstrakt:	Aims: Specific fibroblast markers and in-depth heterogeneity analysis are currently lacking, hindering functional studies in cardiovascular diseases (CVDs). Here, we established cell-type markers and heterogeneity in murine and human arteries and studied the adventitial fibroblast response to CVD and its risk factors hypercholesterolaemia and ageing. Methods and Results: Murine aorta single-cell RNA-sequencing analysis of adventitial mesenchymal cells identified fibroblast-specific markers. Immunohistochemistry and flow cytometry validated platelet-derived growth factor receptor alpha (PDGFRA) and dipeptidase 1 (DPEP1) across human and murine aorta, carotid, and femoral arteries, whereas traditional markers such as the cluster of differentiation (CD)90 and vimentin also marked transgelin+ vascular smooth muscle cells. Next, pseudotime analysis showed multiple fibroblast clusters differentiating along trajectories. Three trajectories, marked by CD55 (Cd55+), Cxcl chemokine 14 (Cxcl14+), and lysyl oxidase (Lox+), were reproduced in an independent RNA-seq dataset. Gene ontology (GO) analysis showed divergent functional profiles of the three trajectories, related to vascular development, antigen presentation, and/or collagen fibril organization, respectively. Trajectory-specific genes included significantly more genes with known genome-wide associations (GWAS) to CVD than expected by chance, implying a role in CVD. Indeed, differential regulation of fibroblast clusters by CVD risk factors was shown in the adventitia of aged C57BL/6J mice, and mildly hypercholesterolaemic LDLR KO mice on chow by flow cytometry. The expansion of collagen-related CXCL14+ and LOX+ fibroblasts in aged and hypercholesterolaemic aortic adventitia, respectively, coincided with increased adventitial collagen. Immunohistochemistry, bulk, and single-cell transcriptomics of human carotid and aorta specimens emphasized translational value as CD55+, CXCL14+ and LOX+ fibroblasts were observed in healthy and atherosclerotic specimens. Also, trajectory-specific gene sets are differentially correlated with human atherosclerotic plaque traits. Conclusion: We provide two adventitial fibroblast-specific markers, PDGFRA and DPEP1, and demonstrate fibroblast heterogeneity in health and CVD in humans and mice. Biological relevance is evident from the regulation of fibroblast clusters by age and hypercholesterolaemia in vivo, associations with human atherosclerotic plaque traits, and enrichment of genes with a GWAS for CVD. Competing Interests: Conflict of interest: None declared. (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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