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Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm.
Pedroza, Albert J; Tashima, Yasushi; Shad, Rohan; Cheng, Paul; Wirka, Robert; Churovich, Samantha; Nakamura, Ken; Yokoyama, Nobu; Cui, Jason Z; Iosef, Cristiana; Hiesinger, William; Quertermous, Thomas; Fischbein, Michael P.
Afiliação
  • Pedroza AJ; From the Department of Cardiothoracic Surgery (A.J.P., Y.T., R.S., S.C., K.N., N.Y., J.Z.C., C.I., W.H., M.P.F.), Stanford University School of Medicine, CA.
  • Tashima Y; From the Department of Cardiothoracic Surgery (A.J.P., Y.T., R.S., S.C., K.N., N.Y., J.Z.C., C.I., W.H., M.P.F.), Stanford University School of Medicine, CA.
  • Shad R; From the Department of Cardiothoracic Surgery (A.J.P., Y.T., R.S., S.C., K.N., N.Y., J.Z.C., C.I., W.H., M.P.F.), Stanford University School of Medicine, CA.
  • Cheng P; Division of Cardiovascular Medicine (P.C., R.W., T.Q.), Stanford University School of Medicine, CA.
  • Wirka R; Division of Cardiovascular Medicine (P.C., R.W., T.Q.), Stanford University School of Medicine, CA.
  • Churovich S; From the Department of Cardiothoracic Surgery (A.J.P., Y.T., R.S., S.C., K.N., N.Y., J.Z.C., C.I., W.H., M.P.F.), Stanford University School of Medicine, CA.
  • Nakamura K; From the Department of Cardiothoracic Surgery (A.J.P., Y.T., R.S., S.C., K.N., N.Y., J.Z.C., C.I., W.H., M.P.F.), Stanford University School of Medicine, CA.
  • Yokoyama N; From the Department of Cardiothoracic Surgery (A.J.P., Y.T., R.S., S.C., K.N., N.Y., J.Z.C., C.I., W.H., M.P.F.), Stanford University School of Medicine, CA.
  • Cui JZ; From the Department of Cardiothoracic Surgery (A.J.P., Y.T., R.S., S.C., K.N., N.Y., J.Z.C., C.I., W.H., M.P.F.), Stanford University School of Medicine, CA.
  • Iosef C; From the Department of Cardiothoracic Surgery (A.J.P., Y.T., R.S., S.C., K.N., N.Y., J.Z.C., C.I., W.H., M.P.F.), Stanford University School of Medicine, CA.
  • Hiesinger W; From the Department of Cardiothoracic Surgery (A.J.P., Y.T., R.S., S.C., K.N., N.Y., J.Z.C., C.I., W.H., M.P.F.), Stanford University School of Medicine, CA.
  • Quertermous T; Division of Cardiovascular Medicine (P.C., R.W., T.Q.), Stanford University School of Medicine, CA.
  • Fischbein MP; From the Department of Cardiothoracic Surgery (A.J.P., Y.T., R.S., S.C., K.N., N.Y., J.Z.C., C.I., W.H., M.P.F.), Stanford University School of Medicine, CA.
Arterioscler Thromb Vasc Biol ; 40(9): 2195-2211, 2020 09.
Article em En | MEDLINE | ID: mdl-32698686
OBJECTIVE: To delineate temporal and spatial dynamics of vascular smooth muscle cell (SMC) transcriptomic changes during aortic aneurysm development in Marfan syndrome (MFS). Approach and Results: We performed single-cell RNA sequencing to study aortic root/ascending aneurysm tissue from Fbn1C1041G/+ (MFS) mice and healthy controls, identifying all aortic cell types. A distinct cluster of transcriptomically modulated SMCs (modSMCs) was identified in adult Fbn1C1041G/+ mouse aortic aneurysm tissue only. Comparison with atherosclerotic aortic data (ApoE-/- mice) revealed similar patterns of SMC modulation but identified an MFS-specific gene signature, including plasminogen activator inhibitor-1 (Serpine1) and Kruppel-like factor 4 (Klf4). We identified 481 differentially expressed genes between modSMC and SMC subsets; functional annotation highlighted extracellular matrix modulation, collagen synthesis, adhesion, and proliferation. Pseudotime trajectory analysis of Fbn1C1041G/+ SMC/modSMC transcriptomes identified genes activated differentially throughout the course of phenotype modulation. While modSMCs were not present in young Fbn1C1041G/+ mouse aortas despite small aortic aneurysm, multiple early modSMCs marker genes were enriched, suggesting activation of phenotype modulation. modSMCs were not found in nondilated adult Fbn1C1041G/+ descending thoracic aortas. Single-cell RNA sequencing from human MFS aortic root aneurysm tissue confirmed analogous SMC modulation in clinical disease. Enhanced expression of TGF-ß (transforming growth factor beta)-responsive genes correlated with SMC modulation in mouse and human data sets. CONCLUSIONS: Dynamic SMC phenotype modulation promotes extracellular matrix substrate modulation and aortic aneurysm progression in MFS. We characterize the disease-specific signature of modSMCs and provide temporal, transcriptomic context to the current understanding of the role TGF-ß plays in MFS aortopathy. Collectively, single-cell RNA sequencing implicates TGF-ß signaling and Klf4 overexpression as potential upstream drivers of SMC modulation.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aneurisma Aórtico / Perfilação da Expressão Gênica / Miócitos de Músculo Liso / Análise de Célula Única / Transcriptoma / Fibrilina-1 / Síndrome de Marfan / Músculo Liso Vascular Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Arterioscler Thromb Vasc Biol Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aneurisma Aórtico / Perfilação da Expressão Gênica / Miócitos de Músculo Liso / Análise de Célula Única / Transcriptoma / Fibrilina-1 / Síndrome de Marfan / Músculo Liso Vascular Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Arterioscler Thromb Vasc Biol Ano de publicação: 2020 Tipo de documento: Article