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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Published in Genes, v. 13, issue 1, 95.

© 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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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.

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The data underlying this article will be made available in the GEO (Gene Expression Omnibus) database.

The following are available online at https://www.mdpi.com/article/10.3390/genes13010095/s1: Figure S1: Individual sample data; Figure S2: Overall gene expression levels in non-immune cells; Figure S3, General cluster identification in immune and non-immune cells in combined samples; Figure S4, Identification of SMC phenotype; Figure S5, Identification of fibroblast phenotype; Figure S6, Identification of endothelial cell and mesenchymal stem cell phenotype; Figure S7, Identification of immune-like non-immune cells; Figure S8, Cell-cell signaling within the TFG-β pathway; Figure S9, Differential expression of genes involved in the control of TFG-β signaling; Table S1, Patient sample information; Table S2, Antibodies used in immunofluorescence; Table S3, Genes associated with TGFB1 in “activated fibroblasts”; Table S4, Genes associated with TGFB1 in “quiescent fibroblasts”.

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