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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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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8774900/
https://www.ncbi.nlm.nih.gov/pubmed/35052435
http://dx.doi.org/10.3390/genes13010095
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author 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.
author_facet 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.
author_sort Dawson, Ashley
collection PubMed
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 (n = 3) and age-matched non-aneurysmal control tissues from cardiac donors and recipients (n = 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 MYOCD and MYH11 in SMCs, and an upregulation of COL1A1/2 in fibroblasts in MFS samples compared to controls. We also examined TGF-β signaling, an important pathway in aortic homeostasis. We found that TGFB1 was significantly upregulated in two fibroblast clusters in MFS tissues. However, TGF-β receptor genes (predominantly TGFBR2) and SMAD genes were downregulated in SMCs, fibroblasts, and ECs in MFS, indicating impairment in TGF-β signaling. In conclusion, despite upregulation of TGFB1, 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.
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spelling pubmed-87749002022-01-21 Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling 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. Genes (Basel) Article 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 (n = 3) and age-matched non-aneurysmal control tissues from cardiac donors and recipients (n = 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 MYOCD and MYH11 in SMCs, and an upregulation of COL1A1/2 in fibroblasts in MFS samples compared to controls. We also examined TGF-β signaling, an important pathway in aortic homeostasis. We found that TGFB1 was significantly upregulated in two fibroblast clusters in MFS tissues. However, TGF-β receptor genes (predominantly TGFBR2) and SMAD genes were downregulated in SMCs, fibroblasts, and ECs in MFS, indicating impairment in TGF-β signaling. In conclusion, despite upregulation of TGFB1, 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. MDPI 2021-12-30 /pmc/articles/PMC8774900/ /pubmed/35052435 http://dx.doi.org/10.3390/genes13010095 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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/).
spellingShingle Article
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.
Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling
title Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling
title_full Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling
title_fullStr Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling
title_full_unstemmed Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling
title_short Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling
title_sort single-cell analysis of aneurysmal aortic tissue in patients with marfan syndrome reveals dysfunctional tgf-β signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8774900/
https://www.ncbi.nlm.nih.gov/pubmed/35052435
http://dx.doi.org/10.3390/genes13010095
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