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

Ashley Dawson; Yanming Li; Yang Li; Pingping Ren; Hernan G. Vasquez; Chen Zhang; Kimberly R. Rebello; Waleed Ageedi; Alon R. Azares; Aladdein Burchett Mattar; Mary Burchett Sheppard; Hong S. Lu; Joseph S. Coselli; Lisa A. Cassis; Alan Daugherty; Ying H. Shen; Scott A. Lemaire

doi:10.3390/genes13010095

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

Ashley Dawson, Yanming Li, Yang Li, Pingping Ren, Hernan G. Vasquez, Chen Zhang, Kimberly R. Rebello, Waleed Ageedi, Alon R. Azares, Aladdein Burchett Mattar, Mary Burchett Sheppard, Hong S. Lu, Joseph S. Coselli, Lisa A. Cassis, Alan Daugherty, Ying H. Shen, Scott A. Lemaire

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

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. Fur-thermore, 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.

Original language	English
Article number	95
Journal	Genes
Volume	13
Issue number	1
DOIs	https://doi.org/10.3390/genes13010095
State	Published - Jan 2022

Bibliographical note

Funding Information:
Funding: This work was supported by grants from the American Heart Association (AHA) Vascular Diseases Strategically Focused Research Networks (SFRN) (AHA18SFRN33960114, AHA18SFRN33960163, and AHA18SFRN33960253) and from the National Institute of Health (NIH; R01HL143359). Dawson was supported by a fellowship award through the University of Kentucky-Baylor College of Medicine Aortopathy Research Center within the AHA SFRN (18SFRN33960114). Ageedi and Rebello were supported by the NIH/National Heart, Lung, and Blood Institute (NHLBI) T32 Research Training Program in Cardiovascular Surgery (T32HL139430). LeMaire’s work was supported in part by the Jimmy and Roberta Howell Professorship in Cardiovascular Surgery at Baylor College of Medicine. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Aneurysm
Marfan syndrome
Molecular biology
Smooth muscle cell differentiation

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.3390/genes13010095

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Dawson, A., Li, Y., Li, Y., Ren, P., Vasquez, H. G., Zhang, C., Rebello, K. R., Ageedi, W., Azares, A. R., Mattar, A. B., Sheppard, M. B., Lu, H. S., Coselli, J. S., Cassis, L. A., Daugherty, A., Shen, Y. H., & Lemaire, S. A. (2022). Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling. Genes, 13(1), Article 95. https://doi.org/10.3390/genes13010095

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

abstract = "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. Fur-thermore, 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.",

keywords = "Aneurysm, Marfan syndrome, Molecular biology, Smooth muscle cell differentiation",

author = "Ashley Dawson and Yanming Li and Yang Li and Pingping Ren and Vasquez, {Hernan G.} and Chen Zhang and Rebello, {Kimberly R.} and Waleed Ageedi and Azares, {Alon R.} and Mattar, {Aladdein Burchett} and Sheppard, {Mary Burchett} and Lu, {Hong S.} and Coselli, {Joseph S.} and Cassis, {Lisa A.} and Alan Daugherty and Shen, {Ying H.} and Lemaire, {Scott A.}",

note = "Funding Information: Funding: This work was supported by grants from the American Heart Association (AHA) Vascular Diseases Strategically Focused Research Networks (SFRN) (AHA18SFRN33960114, AHA18SFRN33960163, and AHA18SFRN33960253) and from the National Institute of Health (NIH; R01HL143359). Dawson was supported by a fellowship award through the University of Kentucky-Baylor College of Medicine Aortopathy Research Center within the AHA SFRN (18SFRN33960114). Ageedi and Rebello were supported by the NIH/National Heart, Lung, and Blood Institute (NHLBI) T32 Research Training Program in Cardiovascular Surgery (T32HL139430). LeMaire{\textquoteright}s work was supported in part by the Jimmy and Roberta Howell Professorship in Cardiovascular Surgery at Baylor College of Medicine. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = jan,

doi = "10.3390/genes13010095",

language = "English",

volume = "13",

number = "1",

}

Dawson, A, Li, Y, Li, Y, Ren, P, Vasquez, HG, Zhang, C, Rebello, KR, Ageedi, W, Azares, AR, Mattar, AB, Sheppard, MB , Lu, HS, Coselli, JS, Cassis, LA , Daugherty, A, Shen, YH & Lemaire, SA 2022, 'Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling', Genes, vol. 13, no. 1, 95. https://doi.org/10.3390/genes13010095

TY - JOUR

T1 - Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling

AU - Dawson, Ashley

AU - Li, Yanming

AU - Li, Yang

AU - Ren, Pingping

AU - Vasquez, Hernan G.

AU - Zhang, Chen

AU - Rebello, Kimberly R.

AU - Ageedi, Waleed

AU - Azares, Alon R.

AU - Mattar, Aladdein Burchett

AU - Sheppard, Mary Burchett

AU - Lu, Hong S.

AU - Coselli, Joseph S.

AU - Cassis, Lisa A.

AU - Daugherty, Alan

AU - Shen, Ying H.

AU - Lemaire, Scott A.

N1 - Funding Information: Funding: This work was supported by grants from the American Heart Association (AHA) Vascular Diseases Strategically Focused Research Networks (SFRN) (AHA18SFRN33960114, AHA18SFRN33960163, and AHA18SFRN33960253) and from the National Institute of Health (NIH; R01HL143359). Dawson was supported by a fellowship award through the University of Kentucky-Baylor College of Medicine Aortopathy Research Center within the AHA SFRN (18SFRN33960114). Ageedi and Rebello were supported by the NIH/National Heart, Lung, and Blood Institute (NHLBI) T32 Research Training Program in Cardiovascular Surgery (T32HL139430). LeMaire’s work was supported in part by the Jimmy and Roberta Howell Professorship in Cardiovascular Surgery at Baylor College of Medicine. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/1

Y1 - 2022/1

N2 - 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. Fur-thermore, 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.

AB - 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. Fur-thermore, 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.

KW - Aneurysm

KW - Marfan syndrome

KW - Molecular biology

KW - Smooth muscle cell differentiation

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DO - 10.3390/genes13010095

M3 - Article

C2 - 35052435

AN - SCOPUS:85122016076

SN - 2073-4425

VL - 13

JO - Genes

JF - Genes

IS - 1

M1 - 95

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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