Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai 200032, China; Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Acta Biomater. 2019 Apr 1;88:540-553. doi: 10.1016/j.actbio.2019.02.024. Epub 2019 Feb 16.
Myocardial infarction (MI) is a primary cardiovascular disease threatening human health and quality of life worldwide. The development of engineered heart tissues (EHTs) as a transplantable artificial myocardium provides a promising therapy for MI. Since most MIs occur at the ventricle, engineering ventricular-specific myocardium is therefore more desirable for future applications. Here, by combining a new macroporous 3D iron oxide scaffold (IOS) with a fixed ratio of human pluripotent stem cell (hPSC)-derived ventricular-specific cardiomyocytes and human umbilical cord-derived mesenchymal stem cells, we constructed a new type of engineered human ventricular-specific heart tissue (EhVHT). The EhVHT promoted expression of cardiac-specific genes, ion exchange, and exhibited a better Ca handling behaviors and normal electrophysiological activity in vitro. Furthermore, when patched on the infarcted area, the EhVHT effectively promoted repair of heart tissues in vivo and facilitated the restoration of damaged heart function of rats with acute MI. Our results show that it is feasible to generate functional human ventricular heart tissue based on hPSC-derived ventricular myocytes for the treatment of ventricular-specific myocardium damage. STATEMENT OF SIGNIFICANCE: We successfully generated highly purified homogenous human ventricular myocytes and developed a method to generate human ventricular-specific heart tissue (EhVHT) based on three-dimensional iron oxide scaffolds. The EhVHT promoted expression of cardiac-specific genes, ion exchange, and exhibited a better Ca handling behaviors and normal electrophysiological activity in vitro. Patching the EhVHT on the infarct area significantly improved cardiac function in rat acute MI models. This EhVHT has a great potential to meet the specific requirements for ventricular damages in most MI cases and for screening drugs specifically targeting ventricular myocardium.
心肌梗死（MI）是一种严重威胁全球人类健康和生活质量的主要心血管疾病。工程心脏组织（EHTs）作为可移植的人工心肌为 MI 提供了一种有前途的治疗方法。由于大多数 MI 发生在心室，因此为了未来的应用，工程化心室特异性心肌更为理想。在这里，我们通过将新型大孔 3D 氧化铁支架（IOS）与一定比例的人多能干细胞（hPSC）衍生的心室特异性心肌细胞和人脐带衍生的间充质干细胞相结合，构建了一种新型工程化人心室特异性心脏组织（EhVHT）。EhVHT 促进了心脏特异性基因的表达、离子交换，并在体外表现出更好的 Ca 处理行为和正常的电生理活性。此外，当贴在梗死区域时，EhVHT 有效地促进了体内心脏组织的修复，并促进了急性 MI 大鼠受损心脏功能的恢复。我们的结果表明，基于 hPSC 衍生的心室肌细胞生成功能性人心室心脏组织用于治疗心室特异性心肌损伤是可行的。
我们成功地产生了高度纯化的同质人心室肌细胞，并开发了一种基于三维氧化铁支架生成人心室特异性心脏组织（EhVHT）的方法。EhVHT 促进了心脏特异性基因的表达、离子交换，并在体外表现出更好的 Ca 处理行为和正常的电生理活性。将 EhVHT 贴在梗死区域显著改善了大鼠急性 MI 模型的心脏功能。这种 EhVHT 具有很大的潜力，可以满足大多数 MI 病例中心室损伤的特定要求，并可用于筛选专门针对心室心肌的药物。
