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 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.