Wang Jiawan, Du Heng, Xie Wanrun, Bi Jinmiao, Zhang Hao, Liu Xu, Wang Yuhan, Zhang Shaolong, Lei Anhua, He Chuting, Yuan Hailong, Zhang Jiahe, Li Yujing, Xu Pengfei, Liu Siqi, Zhou Yanan, Shen Jianghua, Wu Jingdong, Cai Yihong, Yang Chaofan, Li Zeya, Liang Yingxin, Zhao Yang, Zhang Jin, Song Moshi
Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (J. Wang, H.D., J.B., H.Z., X.L., Y.W., C.H., H.Y., Jiahe Zhang, Y. Li, P.X., S.L., Y. Zhou, J.S., C.Y., Z.L., Y. Liang, M.S.).
University of Chinese Academy of Sciences, Beijing, China (J. Wang, H.D., J.B., H.Z., X.L., Y.W., C.H., H.Y., Jiahe Zhang, Y. Li, P.X., S.L., Y. Zhou, J.S., C.Y., Y. Liang, M.S.).
Circ Res. 2024 Dec 6;135(12):1161-1174. doi: 10.1161/CIRCRESAHA.124.325212. Epub 2024 Oct 28.
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.
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.
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.
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.
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，针对心肌纤维化的调节可能具有保护和治疗优势。然而，针对心肌纤维化的有效临床干预和治疗仍然有限。作为一种有前景的嵌合抗原受体（CAR）细胞疗法，CAR巨噬细胞（CAR-Ms）是否可用于治疗I/R尚不清楚。
研究了I/R后小鼠心脏中FAP（成纤维细胞活化蛋白）的表达。制备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。在体外测试了FAP CAR-Ms的吞噬活性。在体内评估了FAP CAR-Ms治疗I/R的疗效和安全性。
早在I/R后3天，FAP在活化的心脏成纤维细胞中显著上调。在证明其吞噬过表达FAP的成纤维细胞的能力后，我们在I/R后3天给小鼠静脉注射FAP CAR-Ms，发现FAP CAR-Ms显著改善了I/R后小鼠的心脏功能并减少了心肌纤维化。在I/R后2周，未在心脏或其他器官中检测到与FAP CAR-Ms相关的毒性。最后，我们发现FAP CAR-Ms对I/R具有长期心脏保护作用。
我们的概念验证研究证明了FAP CAR-Ms在减轻心肌I/R方面的治疗潜力，并可能为治疗一系列具有纤维化表型的心脏病开辟新途径。
