State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China.
Adv Sci (Weinh). 2024 Jun;11(22):e2400444. doi: 10.1002/advs.202400444. Epub 2024 Mar 29.
Aortic root aneurysm is a potentially life-threatening condition that may lead to aortic rupture and is often associated with genetic syndromes, such as Marfan syndrome (MFS). Although studies with MFS animal models have provided valuable insights into the pathogenesis of aortic root aneurysms, this understanding of the transcriptomic and epigenomic landscape in human aortic root tissue remains incomplete. This knowledge gap has impeded the development of effective targeted therapies. Here, this study performs the first integrative analysis of single-nucleus multiomic (gene expression and chromatin accessibility) and spatial transcriptomic sequencing data of human aortic root tissue under healthy and MFS conditions. Cell-type-specific transcriptomic and cis-regulatory profiles in the human aortic root are identified. Regulatory and spatial dynamics during phenotypic modulation of vascular smooth muscle cells (VSMCs), the cardinal cell type, are delineated. Moreover, candidate key regulators driving the phenotypic modulation of VSMC, such as FOXN3, TEAD1, BACH2, and BACH1, are identified. In vitro experiments demonstrate that FOXN3 functions as a novel key regulator for maintaining the contractile phenotype of human aortic VSMCs through targeting ACTA2. These findings provide novel insights into the regulatory and spatial dynamics during phenotypic modulation in the aneurysmal aortic root of humans.
主动脉根部瘤是一种潜在的危及生命的疾病，可能导致主动脉破裂，常与遗传综合征有关，如马凡综合征（MFS）。尽管 MFS 动物模型的研究为主动脉根部瘤的发病机制提供了有价值的见解，但对人类主动脉根部组织的转录组和表观基因组景观的理解仍不完整。这一知识空白阻碍了有效靶向治疗的发展。在这里，这项研究对健康和 MFS 条件下人类主动脉根部组织的单细胞多组学（基因表达和染色质可及性）和空间转录组测序数据进行了首次综合分析。确定了人类主动脉根部的细胞类型特异性转录组和顺式调控特征。描绘了血管平滑肌细胞（VSMC）表型调节过程中的调控和空间动态，VSMC 是主要的细胞类型。此外，还鉴定出了候选关键调节因子，如 FOXN3、TEAD1、BACH2 和 BACH1，它们驱动 VSMC 的表型调节。体外实验表明，FOXN3 通过靶向 ACTA2 作为一种新型关键调节因子，维持人类主动脉 VSMC 的收缩表型。这些发现为人类动脉瘤性主动脉根部表型调节过程中的调控和空间动态提供了新的见解。
