该课题组在27个人类冠状动脉中应用了多组单细胞分析、表位定位和空间转录组学，鉴定成纤维细胞激活蛋白（FAP）是VSMCs调节的标记物。小鼠的谱系追踪显示FAP+细胞起源于Myh11+ VSMCs， CAD患者的FAP PET成像显示斑块摄取。FAP+细胞状态驻留在富含巨噬细胞的新内膜中。在治疗方面，研究人员开发了一种抗FAP双特异性T细胞接触器，通过T细胞克隆扩增减少斑块负担并重塑基质免疫微环境。他们的研究提供了人类CAD的单细胞和空间图谱，建立了FAP作为调节VSMCs的标记物，并强调了对脂质非依赖性靶点的免疫治疗。
据介绍，血管平滑层细胞（VSMC）多样化驱动动脉粥样硬化性冠状动脉疾病（CAD）。控制这些细胞状态转变的机制尚不清楚。
附：英文原文
Title: Targeting modulated vascular smooth muscle cells in atherosclerosis via FAP-directed immunotherapy
Author: Junedh M. Amrute, In-Hyuk Jung, Tracy Yamawaki, Wen-Ling Lin, Andrea Bredemeyer, Johanna Diekmann, Sikander Hayat, Xianglong Zhang, Devin L. Wakefield, Xin Luo, Sidrah Maryam, Gyu Seong Heo, Steven Yang, Chang Jie Mick Lee, Chen Wang, Caroline Chou, Christoph Kuppe, Kevin D. Cook, Atilla Kovacs, Vishnu Chintalgattu, Danielle Pruitt, Jose Barreda, Nathan O. Stitziel, Paul Cheng, Yongjian Liu, Rafael Kramann, Daniel Kreisel, Roger S-Y Foo, Ingrid C. Rulifson, Scott Martin, David Grunert, Melissa Thomas, Jixin Cui, Thomas Quertermous, Frank M. Bengel, Simon Jackson, Chi-Ming Li, Brandon Ason, Kory J. Lavine
Issue&Volume: 2026-01-29
Abstract: Vascular smooth muscle cell (VSMC) diversification drives atherosclerotic coronary artery disease (CAD). Mechanisms governing these cell state transitions remain unclear. We applied multiomic single-cell profiling, epitope mapping, and spatial transcriptomics across 27 human coronary arteries, identifying fibroblast activation protein (FAP) as a marker of modulated VSMCs. Lineage tracing in mice indicated that FAP+ cells originate from Myh11+ VSMCs, and FAP PET imaging in CAD patients showed plaque uptake. FAP+ cells states resided in the macrophage-rich neo-intima. Therapeutically, we developed an anti-FAP bispecific T-cell engager, which reduced plaque burden and remodeled the stromal–immune microenvironment through T-cell clonal expansion. Our study delivers a single-cell and spatial atlas of human CAD, establishes FAP as a marker of modulated VSMCs, and highlights immunotherapy for lipid-independent targets.
DOI: adx1736
Source: https://www.science.org/doi/10.1126/science.adx1736