新型工程化人心室肌补片的构建及其对心肌梗死的疗效评估

Myocardial ischemia leads to the massive death of cardiomyocytes and replacement of the myocardium by fibrotic scar tissues. This causes a severe decrease in myocardium contractility, which usually progressively worsen into life-threatening heart failure. Construction of human engineered heart tissue (hEHT) to implant and replace the scar tissue is one of the promising treatments for myocardial ischemia in the future. Owing to the special anatomy of the coronary arteries, most of the myocardial infarctions (MI) cause damage to the ventricular myocardium. It is, therefore, more appropriate to engineer human ventricular heart tissues for future clinical applications. However, human-engineered ventricular heart tissues (hEVHT) have not been reported yet. By using a novel biodegradable mesoporous iron oxide framework and hiPSCs-derived human cardiomyocytes, we recently successfully prepared engineered heart tissues and performed heart implantation studies. In this proposal, we will make a step forward based on our previous studies. By combining human induced pluripotent stem cells (hiPSCs)-derived human ventricular cardiomyocytes and related cardiac cells with our biodegradable mesoporous iron oxide frameworks, we propose to construct a novel individualized hEVHT and systemically evaluate their effects on acute MI after implantation. These EhVHTs have a great potential to meet the specific requirements for ventricular damages in most MI cases and will be of great value for in vitro drug screening of ventricular-specific reagents.

心肌缺血致心肌细胞大量死亡、心肌组织纤维瘢痕化、收缩功能严重下降，最终进展为危及生命的心力衰竭。以人造心肌组织植入替代梗死区瘢痕组织，是治疗心梗的潜在有效手段。鉴于冠状动脉循行的特殊解剖结构，心肌梗死主要累及心室肌，以人造心室肌组织治疗心梗更为合适。在前期研究中，我们以可降解氧化铁复合介孔材料为支架、hiPSC来源的心肌细胞为种子细胞，制备人造心肌组织并进行体内植入治疗探索，发现其有效促进了大鼠心梗局部病灶的 血管新生;此外，我们还以hiPSC定向分化获得纯度>97%的人心室肌细胞。本项目拟在此基础上，以高纯度人心室肌细胞等为种子细胞、壳聚糖-氧化铁复合介孔材料为支架，构建新型个体化人造人心室肌补片组织，评价其植入体内后对急性心肌梗死的治疗效果。项目研究所获结果将为个体化人心室肌组织的制备及临床应用提供方法技术，有助于解决心肌梗死及心衰治疗难题。

心肌缺血致心肌细胞大量死亡、心肌组织纤维瘢痕化、收缩功能严重下降，最终进展为危及生命的心力衰竭。以人造心肌组织植入替代梗死区瘢痕组织，是治疗心梗的潜在有效手段。 鉴于冠状动脉循行的特殊解剖结构，心肌梗死主要累及心室肌，以人造心室肌组织治疗心梗更为合适。同时，可注射的支架材料作为细胞输送的载体，能够为移植细胞提供一个三维包裹的作用，提高细胞在治疗靶点的滞留时间和存活数量。在此背景下，我们采用高分子透明质酸和明胶这两种天然材料作为主要基体材料，通过对透明质酸进行氧化处理以及对明胶进行接枝处理，制备成无需UV交联的新型可注射成型水凝胶。结合我们高纯度hiPSC定向分化来源的人类心室肌细胞作为种子细胞，我们构建了一种新型可注射工程化人类心室肌组织，该新型可注射工程化人类心室肌组织在体外能够维持心肌细胞收缩，维持其正常的钙处理能力。此外，将该组织移植到大鼠体内，能有效改善心功能、缩小梗死面积、增加室壁厚度，改善心脏心肌组织应变力，并促进梗死边缘区血管新生。因此，我们构建的新型可注射工程化人类心室肌组织在心肌梗死的治疗方面具有很大的应用价值。