血管平滑肌
免疫疗法
医学
平滑肌
癌症研究
免疫学
内科学
免疫系统
作者
Junedh Amrute,In‐Hyuk Jung,Tracy Yamawaki,Andrea Bredemeyer,Johanna Diekmann,Sikander Hayat,Wen-Ling Lin,Xianglong Zhang,Xin Luo,Sidrah Maryam,Gyu Seong Heo,Steven Yang,Chang Jie Mick Lee,Caroline Chou,Christoph Kuppe,Kevin D. Cook,Attila Kovács,Vishnu Chintalgattu,Danielle Pruitt,Jose Barreda
标识
DOI:10.1101/2025.03.03.641211
摘要
Abstract Vascular smooth muscle cell (VSMC) and immune cell diversification play a central role in driving atherosclerotic coronary artery disease (CAD) 1–3 . However, the molecular mechanisms governing cell state transitions within the neo-intima in human CAD remain poorly understood, and no lipid-independent therapies are currently approved for its treatment. Here, we performed multi-omic single-cell gene expression profiling, epitope mapping, and spatial transcriptomics from 27 human coronary arteries. Our analysis identified fibroblast activation protein (FAP) as a marker of modulated VSMCs within the neo-intima. Genetic lineage tracing in mice confirmed that FAP⁺ cells in the plaque originate from medial VSMCs. Additionally, non-invasive positron emission tomography (PET) imaging in patients with CAD revealed focal FAP uptake in atherosclerotic lesions. Spatial transcriptomics further delineated the distinct localization of VSMC and immune cell subsets within plaques, with FAP⁺ states enriched in the neo-intima. To explore the therapeutic potential of targeting de-differentiated VSMCs, we developed an anti-FAP bispecific T-cell engager (BiTE) and demonstrated that it significantly reduced the plaque burden in multiple mouse models of atherosclerosis. Collectively, our study provides the first single-cell and spatially resolved map of human CAD, establishes FAP as a marker of modulated smooth muscle cells, and demonstrates the broader potential of immunotherapeutics for lipid independent targets in atherosclerotic CAD.
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