CAR-Macrophage Therapy Alleviates Myocardial Ischemia-Reperfusion Injury.

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Circulation research Pub Date : 2024-12-06 Epub Date: 2024-10-28 DOI:10.1161/CIRCRESAHA.124.325212
Jiawan Wang, Heng Du, Wanrun Xie, Jinmiao Bi, Hao Zhang, Xu Liu, Yuhan Wang, Shaolong Zhang, Anhua Lei, Chuting He, Hailong Yuan, Jiahe Zhang, Yujing Li, Pengfei Xu, Siqi Liu, Yanan Zhou, Jianghua Shen, Jingdong Wu, Yihong Cai, Chaofan Yang, Zeya Li, Yingxin Liang, Yang Zhao, Jin Zhang, Moshi Song
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引用次数: 0

Abstract

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.

CAR-巨噬细胞疗法缓解心肌缺血再灌注损伤
背景:鉴于人们日益认识到心肌缺血再灌注损伤(I/R)后过度心肌纤维化对病理重塑的不利影响,以调节心肌纤维化为目标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疗法仍然有限。作为一种前景广阔的嵌合抗原受体(CAR)细胞疗法,CAR巨噬细胞(CAR-Ms)能否用于治疗I/R仍不清楚:方法:研究了I/R后小鼠心脏中FAP(成纤维细胞活化蛋白)的表达。方法:研究了FAP(成纤维细胞活化蛋白)在I/R后小鼠心脏中的表达情况,生成了针对I/R后小鼠心脏中FAP表达的成纤维细胞的FAP CAR-Ms。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 的有效性和安全性:结果:早在I/R后3天,FAP就在活化的心脏成纤维细胞中明显上调。在证明其吞噬FAP表达过高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能显著改善I/R后小鼠的心功能并减少心肌纤维化。I/R 后 2 周,在心脏或其他器官中未发现与 FAP CAR-Ms 相关的毒性反应。最后,我们还发现FAP CAR-Ms能长期保护心脏免受I/R损伤: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,并有可能为治疗包括纤维化表型在内的一系列心脏疾病开辟新的途径。
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来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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