靶向活化成纤维细胞CAR-T细胞通过分泌CCL24促进心肌梗死后心肌细胞再生的机制研究

心肌纤维化是心肌梗死进展为心力衰竭的直接原因。但目前纤维化治疗手段缺乏，且单纯抗纤维化增加心脏破裂风险。理想治疗手段为抑制纤维化同时促进心肌再生。我们前期运用单细胞测序发现并验证了Cthrc1+成纤维细胞是参与心肌梗死后纤维化最主要的亚群。同时，既往心肌再生的研究发现CCL24能促进IGF2BP3表达，而IGF2BP3是心肌细胞增殖的强调控因子，但调控机制不明。根据现有文献和前期研究，我们推测IGF2BP3可通过RNA表观遗传调节增强Ybx1信号促进成年心肌细胞增殖。鉴于嵌合抗原受体T细胞（CAR-T）在靶向杀伤肿瘤细胞中巨大优势，结合心肌纤维化自身特点，我们设计了一种以活化的成纤维细胞标志物Cthrc1为靶抗原并释放CCL24因子的新型CAR-T细胞，设想其在靶向抗纤维化同时，激活IGF2BP3-Ybx1通路促进心肌再生，改善心功能。本课题的CAR-T治疗理念可推广用于其他心血管疾病。

The progression of myocardial infarction to heart failure is directly related to myocardial fibrosis. However, targeted anti-fibrosis means are lacking currently, and anti-fibrosis alone increases the risk of heart rupture. The ideal treatment is to promote myocardial regeneration while targeting against fibrosis. In our previous study, we used single-cell sequencing to compare the transcriptome of collagen-producing cardiac fibroblasts in the myocardial infarction group and the sham operation group, and verified that Collagen Triple Helix Repeat Containing 1 (Cthrc1) is the most important subgroup of fibroblasts involved in myocardial fibrosis after myocardial infarction. Meanwhile, previous studies on cardiac regeneration have shown that the immune-related gene C-C motif chemokine ligand 24 (CCL24) can promote the secretion of insulin-like growth factor 2 messenger RNA binding protein 3 (Igf2bp3), which is a strong regulator of cardiac cell proliferation, whereas the regulatory mechanism is unclear. According to the existing literature and the results of our previous studies, we speculated that Igf2bp3 can promote the proliferation of adult cardiomyocytes and induce myocardial regeneration by enhancing YBX1 signal. Given the huge advantage of chimeric T cell antigen receptors (CAR) in the killing cells in a target way, we have designed a new kind of CAR-T cells, which target Cthrc1 as markers for activated fibroblasts and release CCL24. We assume that it activates Igf2bp3-YBX1 pathway to promote the proliferation of adult cardiomyocytes and improve cardiac function while targeting anti-fibrosis, improve heart function. We aim to identify the curative effect in vivo.