Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling

The molecular and cellular processes leading to aortic aneurysm development in Marfan syndrome (MFS) remain poorly understood. In this study, we examined the changes of aortic cell populations and gene expression in MFS by performing single-cell RNA sequencing (scRNA seq) on ascending aortic aneurys...

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Veröffentlicht in:Genes 2021-12, Vol.13 (1), p.95
Hauptverfasser: Dawson, Ashley, Li, Yanming, Li, Yang, Ren, Pingping, Vasquez, Hernan G, Zhang, Chen, Rebello, Kimberly R, Ageedi, Waleed, Azares, Alon R, Mattar, Aladdein Burchett, Sheppard, Mary Burchett, Lu, Hong S, Coselli, Joseph S, Cassis, Lisa A, Daugherty, Alan, Shen, Ying H, LeMaire, Scott A
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container_issue 1
container_start_page 95
container_title Genes
container_volume 13
creator Dawson, Ashley
Li, Yanming
Li, Yang
Ren, Pingping
Vasquez, Hernan G
Zhang, Chen
Rebello, Kimberly R
Ageedi, Waleed
Azares, Alon R
Mattar, Aladdein Burchett
Sheppard, Mary Burchett
Lu, Hong S
Coselli, Joseph S
Cassis, Lisa A
Daugherty, Alan
Shen, Ying H
LeMaire, Scott A
description The molecular and cellular processes leading to aortic aneurysm development in Marfan syndrome (MFS) remain poorly understood. In this study, we examined the changes of aortic cell populations and gene expression in MFS by performing single-cell RNA sequencing (scRNA seq) on ascending aortic aneurysm tissues from patients with MFS ( = 3) and age-matched non-aneurysmal control tissues from cardiac donors and recipients ( = 4). The expression of key molecules was confirmed by immunostaining. We detected diverse populations of smooth muscle cells (SMCs), fibroblasts, and endothelial cells (ECs) in the aortic wall. Aortic tissues from MFS showed alterations of cell populations with increased de-differentiated proliferative SMCs compared to controls. Furthermore, there was a downregulation of and in SMCs, and an upregulation of in fibroblasts in MFS samples compared to controls. We also examined TGF-β signaling, an important pathway in aortic homeostasis. We found that was significantly upregulated in two fibroblast clusters in MFS tissues. However, TGF-β receptor genes (predominantly ) and genes were downregulated in SMCs, fibroblasts, and ECs in MFS, indicating impairment in TGF-β signaling. In conclusion, despite upregulation of , the rest of the canonical TGF-β pathway and mature SMCs were consistently downregulated in MFS, indicating a potential compromise of TGF-β signaling and lack of stimulus for SMC differentiation.
doi_str_mv 10.3390/genes13010095
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In this study, we examined the changes of aortic cell populations and gene expression in MFS by performing single-cell RNA sequencing (scRNA seq) on ascending aortic aneurysm tissues from patients with MFS ( = 3) and age-matched non-aneurysmal control tissues from cardiac donors and recipients ( = 4). The expression of key molecules was confirmed by immunostaining. We detected diverse populations of smooth muscle cells (SMCs), fibroblasts, and endothelial cells (ECs) in the aortic wall. Aortic tissues from MFS showed alterations of cell populations with increased de-differentiated proliferative SMCs compared to controls. Furthermore, there was a downregulation of and in SMCs, and an upregulation of in fibroblasts in MFS samples compared to controls. We also examined TGF-β signaling, an important pathway in aortic homeostasis. We found that was significantly upregulated in two fibroblast clusters in MFS tissues. However, TGF-β receptor genes (predominantly ) and genes were downregulated in SMCs, fibroblasts, and ECs in MFS, indicating impairment in TGF-β signaling. In conclusion, despite upregulation of , the rest of the canonical TGF-β pathway and mature SMCs were consistently downregulated in MFS, indicating a potential compromise of TGF-β signaling and lack of stimulus for SMC differentiation.</description><identifier>ISSN: 2073-4425</identifier><identifier>EISSN: 2073-4425</identifier><identifier>DOI: 10.3390/genes13010095</identifier><identifier>PMID: 35052435</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Adult ; Antibodies ; Aortic Aneurysm, Thoracic - diagnosis ; Aortic Aneurysm, Thoracic - etiology ; Aortic Aneurysm, Thoracic - metabolism ; Aortic aneurysms ; Case-Control Studies ; Cell Differentiation ; Collagen (type I) ; Correlation analysis ; Endothelial cells ; Female ; Fibroblasts ; Gene expression ; Gene Expression Regulation ; Genomes ; Genomics ; Homeostasis ; Humans ; Localization ; Male ; Marfan syndrome ; Marfan Syndrome - complications ; Microscopy ; Mutation ; Quality control ; Quorum sensing ; Receptors, Transforming Growth Factor beta - genetics ; Receptors, Transforming Growth Factor beta - metabolism ; Signal Transduction ; Single-Cell Analysis ; Smad protein ; Smooth muscle ; Transforming Growth Factor beta - genetics ; Transforming Growth Factor beta - metabolism ; Transforming growth factor-b ; Transforming growth factor-b1 ; Young Adult</subject><ispartof>Genes, 2021-12, Vol.13 (1), p.95</ispartof><rights>2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). 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source MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; PubMed; EZB Electronic Journals Library; PubMed Central Open Access
subjects Adult
Antibodies
Aortic Aneurysm, Thoracic - diagnosis
Aortic Aneurysm, Thoracic - etiology
Aortic Aneurysm, Thoracic - metabolism
Aortic aneurysms
Case-Control Studies
Cell Differentiation
Collagen (type I)
Correlation analysis
Endothelial cells
Female
Fibroblasts
Gene expression
Gene Expression Regulation
Genomes
Genomics
Homeostasis
Humans
Localization
Male
Marfan syndrome
Marfan Syndrome - complications
Microscopy
Mutation
Quality control
Quorum sensing
Receptors, Transforming Growth Factor beta - genetics
Receptors, Transforming Growth Factor beta - metabolism
Signal Transduction
Single-Cell Analysis
Smad protein
Smooth muscle
Transforming Growth Factor beta - genetics
Transforming Growth Factor beta - metabolism
Transforming growth factor-b
Transforming growth factor-b1
Young Adult
title Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling
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