BACKGROUND Given the growing acknowledgment of the detrimental effects of excessive myocardial fibrosis on pathological remodeling after myocardial ischemia-reperfusion injury (I/R), targeting the modulation of myocardial fibrosis may offer protective and therapeutic advantages. However, effective clinical interventions and therapies that target myocardial fibrosis remain limited. As a promising chimeric antigen receptor (CAR) cell therapy, whether CAR macrophages (CAR-Ms) can be used to treat I/R remains unclear. METHODS The expression of FAP (fibroblast activation protein) was studied in mouse hearts after I/R. FAP CAR-Ms were generated to target FAP-expressing cardiac fibroblasts in mouse hearts after I/R. The phagocytosis activity of FAP CAR-Ms was tested in vitro. The efficacy and safety of FAP CAR-Ms in treating I/R were evaluated in vivo. RESULTS FAP was significantly upregulated in activated cardiac fibroblasts as early as 3 days after I/R. Upon demonstrating their ability to engulf FAP-overexpressing fibroblasts, we intravenously administered FAP CAR-Ms to mice at 3 days after I/R and found that FAP CAR-Ms significantly improved cardiac function and reduced myocardial fibrosis in mice after I/R. No toxicities associated with FAP CAR-Ms were detected in the heart or other organs at 2 weeks after I/R. Finally, we found that FAP CAR-Ms conferred long-term cardioprotection against I/R. CONCLUSIONS Our proof-of-concept study demonstrates the therapeutic potential of FAP CAR-Ms in alleviating myocardial I/R and potentially opens new avenues for the treatment of a range of heart diseases that include a fibrotic phenotype.

中文翻译：

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CAR 巨噬细胞疗法可减轻心肌缺血再灌注损伤。


背景 鉴于人们越来越认识到过度心肌纤维化对心肌缺血再灌注损伤 （I/R） 后病理重塑的有害影响，靶向调节心肌纤维化可能提供保护和治疗优势。然而，针对心肌纤维化的有效临床干预和疗法仍然有限。作为一种有前途的嵌合抗原受体 （CAR） 细胞疗法，CAR 巨噬细胞 （CAR-M） 是否可用于治疗 I/R 仍不清楚。方法 研究 I/R 后 FAP （FIBROBLAST ACTIVATION PROTEIN） 在小鼠心脏中的表达，生成 FAP CAR-Ms 以靶向 I/R 后小鼠心脏中表达 FAP 的心脏成纤维细胞。体外检测 FAP CAR-Ms 的吞噬活性。在体内评价 FAP CAR-Ms 治疗 I/R 的有效性和安全性。结果 早在 I/R 后 3 天，活化的心脏成纤维细胞中 FAP 就显著上调。在证明它们能够吞噬 FAP 过表达的成纤维细胞后，我们在 I/R 后 3 天对小鼠静脉注射 FAP CAR-Ms，发现 FAP CAR-Ms 显着改善了 I/R 后小鼠的心脏功能并减少了心肌纤维化。I/R 后 2 周在心脏或其他器官中未检测到与 FAP CAR-Ms 相关的毒性。最后，我们发现 FAP CAR-Ms 具有针对 I/R 的长期心脏保护作用。结论 我们的概念验证研究表明 FAP CAR-Ms 在缓解心肌 I/R 方面的治疗潜力，并可能为治疗包括纤维化表型在内的一系列心脏病开辟新途径。