In vivo visualization and molecular targeting of the cardiac conduction system.
In vivo visualization and molecular targeting of the cardiac conduction system.
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DOI：
10.1172/jci156955
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发表时间：
2022-10-17
影响因子：
15.9
通讯作者：
Wu, Sean M.
中科院分区：
文献类型：
--
作者：
Goodyer, William R.;Beyersdorf, Benjamin M.;Duan, Lauren;van den Berg, Nynke S.;Mantri, Sruthi;Galdos, Francisco X.;Puluca, Nazan;Buikema, Jan W.;Lee, Soah;Salmi, Darren;Robinson, Elise R.;Rogalla, Stephan;Cogan, Dillon P.;Khosla, Chaitan;Rosenthal, Eben L.;Wu, Sean M.
心脏传导系统（CCS）是一个嵌入心脏内的特殊细胞网络，与周围的心肌组织无法区分，心脏传导系统（CCS）的意外损伤是心脏手术的主要并发症。在这里，我们通过工程化针对CCS的靶向抗体-染料缀合物解决了这种未满足的需求，允许在小鼠中单次静脉内注射后在体内可视化CCS。这些光学成像工具显示出高灵敏度、特异性和分辨率，对CCS功能无不良影响。此外，为了创造用于人类的可行原型，我们产生了类似地以高特异性靶向CCS的全人单克隆Fab。我们证明，当与替代货物缀合时，该Fab也可用于调节体内CCS生物学，为靶向心脏治疗提供了原理证明。最后，在进行差异基因表达分析的整个鼠CCS在单细胞分辨率，我们发现并验证了一套额外的细胞表面标记物，可用于分子靶向的CCS的不同的子组件，每个容易不同的危及生命的心律失常。这些发现为靶向CCS的转化方法奠定了基础，用于心胸外科手术、心脏成像和心律失常管理中的可视化和治疗。
Accidental injury to the cardiac conduction system (CCS), a network of specialized cells embedded within the heart and indistinguishable from the surrounding heart muscle tissue, is a major complication in cardiac surgeries. Here, we addressed this unmet need by engineering targeted antibody-dye conjugates directed against the CCS, allowing for the visualization of the CCS in vivo following a single intravenous injection in mice. These optical imaging tools showed high sensitivity, specificity, and resolution, with no adverse effects on CCS function. Further, with the goal of creating a viable prototype for human use, we generated a fully human monoclonal Fab that similarly targets the CCS with high specificity. We demonstrate that, when conjugated to an alternative cargo, this Fab can also be used to modulate CCS biology in vivo, providing a proof of principle for targeted cardiac therapeutics. Finally, in performing differential gene expression analyses of the entire murine CCS at single-cell resolution, we uncovered and validated a suite of additional cell surface markers that can be used to molecularly target the distinct subcomponents of the CCS, each prone to distinct life-threatening arrhythmias. These findings lay the foundation for translational approaches targeting the CCS for visualization and therapy in cardiothoracic surgery, cardiac imaging, and arrhythmia management.
DOI：
10.1016/j.suronc.2018.04.004
发表时间：
2018-06
期刊：
Surgical oncology
影响因子：
--
作者：
Prince AC;Moore LS;Tipirneni KE;Ramesh T;Limdi MA;Bevans SL;Walsh EM;Greene B;Rosenthal EL;Warram JM
通讯作者：
Warram JM