Bashore Alexander C, Coronel Johana, Xue Chenyi, Zhu Lucie Y, Reilly Muredach P
Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.C.B.).
Division of Cardiology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY (J.C., C.X., L.Y.Z., M.P.R.).
Arterioscler Thromb Vasc Biol. 2025 Aug;45(8):1389-1397. doi: 10.1161/ATVBAHA.124.322370. Epub 2025 Jun 12.
Atherosclerosis involves complex interactions between lipids, immune cells, vascular smooth muscle cells, and fibroblasts within the arterial wall. While significant advances in single-cell technologies have shed light on the roles of immune cells and vascular smooth muscle cells in plaque development, fibroblasts remain underexplored, leaving critical gaps in understanding their contributions to disease progression and plaque stability. Comprehensive characterization of fibroblast phenotypes in atherosclerosis is essential to unravel their diverse functions and to distinguish between subsets that may play protective versus pathogenic roles in the disease process.
Here, we utilized cellular indexing of transcriptomes and epitopes by sequencing to comprehensively profile fibroblast diversity in a mouse model of atherosclerosis. Mice were fed an atherogenic diet for 0, 8, 19, and 26 weeks, representing distinct stages of disease progression, enabling a detailed phenotypic characterization of fibroblasts throughout the course of atherosclerosis development.
We identified 4 distinct fibroblast subpopulations, including a myofibroblast population closely resembling vascular smooth muscle cell-derived chondromyocytes. The proportions of these fibroblast subsets exhibited a modest decline as atherosclerosis progressed. Through multimodal analysis, we identified CD26 (cluster of differentiation) as a highly expressed and specific marker for one of these fibroblast subpopulations, distinguishing it from other subsets. Using a combination of flow cytometry and immunohistochemistry, we demonstrated that CD26 fibroblasts predominantly reside in the adventitia of healthy arteries. During atherosclerosis progression, these cells expand into the intima and primarily localize within the fibrous cap of the lesion.
Our multiomic analysis highlights the phenotypic diversity and dynamic changes of fibroblasts during atherosclerosis progression. Among these, CD26 fibroblasts emerge as a distinct subpopulation that expands within atherosclerotic lesions and may play a critical role in promoting plaque stability through their migration into the fibrous cap.
动脉粥样硬化涉及动脉壁内脂质、免疫细胞、血管平滑肌细胞和成纤维细胞之间的复杂相互作用。虽然单细胞技术取得了重大进展，揭示了免疫细胞和血管平滑肌细胞在斑块形成中的作用，但成纤维细胞仍未得到充分研究，在理解它们对疾病进展和斑块稳定性的贡献方面存在关键空白。全面表征动脉粥样硬化中成纤维细胞的表型对于阐明其多样功能以及区分在疾病过程中可能发挥保护作用与致病作用的亚群至关重要。
在此，我们利用测序对转录组和表位进行细胞索引，以全面描绘动脉粥样硬化小鼠模型中成纤维细胞的多样性。给小鼠喂食致动脉粥样硬化饮食0、8、19和26周，代表疾病进展的不同阶段，从而能够在动脉粥样硬化发展过程中对成纤维细胞进行详细的表型特征分析。
我们鉴定出4种不同的成纤维细胞亚群，包括一个与血管平滑肌细胞衍生的软骨肌细胞非常相似的肌成纤维细胞群体。随着动脉粥样硬化的进展，这些成纤维细胞亚群的比例略有下降。通过多模态分析，我们确定CD26（分化簇）是其中一个成纤维细胞亚群的高表达特异性标志物，可将其与其他亚群区分开来。通过流式细胞术和免疫组织化学相结合的方法，我们证明CD26成纤维细胞主要存在于健康动脉的外膜中。在动脉粥样硬化进展过程中，这些细胞向内膜扩展并主要定位于病变的纤维帽内。
我们的多组学分析突出了动脉粥样硬化进展过程中成纤维细胞的表型多样性和动态变化。其中，CD26成纤维细胞作为一个独特的亚群出现，在动脉粥样硬化病变中扩增，并可能通过迁移到纤维帽中在促进斑块稳定性方面发挥关键作用。
