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. 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.
Highlights
Marfan syndrome (MFS), an autosomal dominant disease, is associated with aortic aneurysms predominantly involving the aortic root [1]
We identified major cell groups in the aortic wall by using known markers (Supplementary Material online, Figure S3) for smooth muscle cells (SMCs) (SMTN, MYH11), fibroblasts, endothelial cells (ECs) (PECAM11, POSTN, VWF), monocytes and macrophages (CD14, CD68), CD8 T cells (CD8A, CD8B), natural killer cells (KLRC1), and mast cells (CPA3 and TPSB2)
Several understand thegfeancetsoruspdsrtriveainmg oafoErtRicKd,iisnecalsuediinngMSFHSC, a1n, dSOwSe1,haynpdotRhaessi(zKeRdAthSa),twceelrle-sdpoew- nregulated in cific changes inMcFelSl asicgronsaslimngualtnipdledeclvuesltoeprsm. ent due to FBN1 mutations in MFS may lead
Summary
Marfan syndrome (MFS), an autosomal dominant disease, is associated with aortic aneurysms predominantly involving the aortic root [1]. Studies have indicated changes in the expression of contractile and extracellular matrix (ECM) genes [5,6] and alterations in SMC appearance [7]. New sequencing technologies, such as single-cell RNA (scRNA) sequencing, have provided a more precise understanding of the range of SMC phenotypes [8]. We used scRNA sequencing to better understand the non-immune cell populations in the aortic wall in MFS. We hypothesized that, compared with control cells, non-immune cells in aneurysmal tissue from patients with MFS would show changes in phenotype and cell-specific gene expression that are detectable by singlecell transcriptome analysis
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