Aortic Cellular Diversity and Quantitative Genome-Wide Association Study Trait Prioritization Through Single-Nuclear RNA Sequencing of the Aneurysmal Human Aorta.

Autor:	Chou EL; Division of Vascular and Endovascular Surgery (E.L.C.), Massachusetts General Hospital, Boston.; Cardiovascular Research Center (E.L.C., J.P.P., C.L.L.C., E.M.I., P.T.E., M.E.L.), Massachusetts General Hospital, Boston.; Cardiovascular Disease Initiative (E.L.C., M.C., B.S., J.P.P., M.N., C.N., P.T.E., M.E.L.), Broad Institute, Cambridge, MA., Chaffin M; Cardiovascular Disease Initiative (E.L.C., M.C., B.S., J.P.P., M.N., C.N., P.T.E., M.E.L.), Broad Institute, Cambridge, MA.; Precision Cardiology Laboratory (M.C., B.S., J.P.P., C.N., P.T.E.), Broad Institute, Cambridge, MA., Simonson B; Cardiovascular Disease Initiative (E.L.C., M.C., B.S., J.P.P., M.N., C.N., P.T.E., M.E.L.), Broad Institute, Cambridge, MA.; Precision Cardiology Laboratory (M.C., B.S., J.P.P., C.N., P.T.E.), Broad Institute, Cambridge, MA., Pirruccello JP; Cardiology Division (J.P.P., C.L.L.C., E.M.I., P.T.E., M.E.L.), Massachusetts General Hospital, Boston.; Cardiovascular Research Center (E.L.C., J.P.P., C.L.L.C., E.M.I., P.T.E., M.E.L.), Massachusetts General Hospital, Boston.; Demoulas Center for Cardiac Arrhythmias (J.P.P., M.N., P.T.E.), Massachusetts General Hospital, Boston.; Cardiovascular Disease Initiative (E.L.C., M.C., B.S., J.P.P., M.N., C.N., P.T.E., M.E.L.), Broad Institute, Cambridge, MA.; Precision Cardiology Laboratory (M.C., B.S., J.P.P., C.N., P.T.E.), Broad Institute, Cambridge, MA., Akkad AD; Precision Cardiology Laboratory, Bayer US LLC, Cambridge, MA (A.-D.A., C.K.)., Nekoui M; Demoulas Center for Cardiac Arrhythmias (J.P.P., M.N., P.T.E.), Massachusetts General Hospital, Boston.; Cardiovascular Disease Initiative (E.L.C., M.C., B.S., J.P.P., M.N., C.N., P.T.E., M.E.L.), Broad Institute, Cambridge, MA., Lino Cardenas CL; Cardiology Division (J.P.P., C.L.L.C., E.M.I., P.T.E., M.E.L.), Massachusetts General Hospital, Boston.; Cardiovascular Research Center (E.L.C., J.P.P., C.L.L.C., E.M.I., P.T.E., M.E.L.), Massachusetts General Hospital, Boston., Bedi KC Jr; Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.C.B., K.B.M.)., Nash C; Cardiovascular Disease Initiative (E.L.C., M.C., B.S., J.P.P., M.N., C.N., P.T.E., M.E.L.), Broad Institute, Cambridge, MA.; Precision Cardiology Laboratory (M.C., B.S., J.P.P., C.N., P.T.E.), Broad Institute, Cambridge, MA., Juric D; Cancer Center (D.J.), Massachusetts General Hospital, Boston., Stone JR; Department of Pathology (J.R.S.), Massachusetts General Hospital, Boston., Isselbacher EM; Cardiology Division (J.P.P., C.L.L.C., E.M.I., P.T.E., M.E.L.), Massachusetts General Hospital, Boston.; Cardiovascular Research Center (E.L.C., J.P.P., C.L.L.C., E.M.I., P.T.E., M.E.L.), Massachusetts General Hospital, Boston.; Thoracic Aortic Center (E.M.I., M.E.L.), Massachusetts General Hospital, Boston., Margulies KB; Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.C.B., K.B.M.)., Klattenhoff C; Precision Cardiology Laboratory, Bayer US LLC, Cambridge, MA (A.-D.A., C.K.)., Ellinor PT; Cardiology Division (J.P.P., C.L.L.C., E.M.I., P.T.E., M.E.L.), Massachusetts General Hospital, Boston.; Cardiovascular Research Center (E.L.C., J.P.P., C.L.L.C., E.M.I., P.T.E., M.E.L.), Massachusetts General Hospital, Boston.; Demoulas Center for Cardiac Arrhythmias (J.P.P., M.N., P.T.E.), Massachusetts General Hospital, Boston.; Cardiovascular Disease Initiative (E.L.C., M.C., B.S., J.P.P., M.N., C.N., P.T.E., M.E.L.), Broad Institute, Cambridge, MA.; Precision Cardiology Laboratory (M.C., B.S., J.P.P., C.N., P.T.E.), Broad Institute, Cambridge, MA., Lindsay ME; Division of Vascular and Endovascular Surgery (E.L.C.), Massachusetts General Hospital, Boston.; Cardiology Division (J.P.P., C.L.L.C., E.M.I., P.T.E., M.E.L.), Massachusetts General Hospital, Boston.; Cardiovascular Research Center (E.L.C., J.P.P., C.L.L.C., E.M.I., P.T.E., M.E.L.), Massachusetts General Hospital, Boston.; Thoracic Aortic Center (E.M.I., M.E.L.), Massachusetts General Hospital, Boston.; Cardiovascular Disease Initiative (E.L.C., M.C., B.S., J.P.P., M.N., C.N., P.T.E., M.E.L.), Broad Institute, Cambridge, MA.
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2022 Nov; Vol. 42 (11), pp. 1355-1374. Date of Electronic Publication: 2022 Sep 29.
DOI:	10.1161/ATVBAHA.122.317953
Abstrakt:	Background: Mural cells in ascending aortic aneurysms undergo phenotypic changes that promote extracellular matrix destruction and structural weakening. To explore this biology, we analyzed the transcriptional features of thoracic aortic tissue. Methods: Single-nuclear RNA sequencing was performed on 13 samples from human donors, 6 with thoracic aortic aneurysm, and 7 without aneurysm. Individual transcriptomes were then clustered based on transcriptional profiles. Clusters were used for between-disease differential gene expression analyses, subcluster analysis, and analyzed for intersection with genetic aortic trait data. Results: We sequenced 71 689 nuclei from human thoracic aortas and identified 14 clusters, aligning with 11 cell types, predominantly vascular smooth muscle cells (VSMCs) consistent with aortic histology. With unbiased methodology, we found 7 vascular smooth muscle cell and 6 fibroblast subclusters. Differentially expressed genes analysis revealed a vascular smooth muscle cell group accounting for the majority of differential gene expression. Fibroblast populations in aneurysm exhibit distinct behavior with almost complete disappearance of quiescent fibroblasts. Differentially expressed genes were used to prioritize genes at aortic diameter and distensibility genome-wide association study loci highlighting the genes JUN, LTBP4 (latent transforming growth factor beta-binding protein 1), and IL34 (interleukin 34) in fibroblasts, ENTPD1, PDLIM5 (PDZ and LIM domain 5), ACTN4 (alpha-actinin-4), and GLRX in vascular smooth muscle cells, as well as LRP1 in macrophage populations. Conclusions: Using nuclear RNA sequencing, we describe the cellular diversity of healthy and aneurysmal human ascending aorta. Sporadic aortic aneurysm is characterized by differential gene expression within known cellular classes rather than by the appearance of novel cellular forms. Single-nuclear RNA sequencing of aortic tissue can be used to prioritize genes at aortic trait loci.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu