Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, CA 94305, USA; Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, San Diego, CA, USA.
Cell Rep. 2020 Jul 21;32(3):107925. doi: 10.1016/j.celrep.2020.107925.
Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have enormous potential for the study of human cardiac disorders. However, their physiological immaturity severely limits their utility as a model system and their adoption for drug discovery. Here, we describe maturation media designed to provide oxidative substrates adapted to the metabolic needs of human iPSC (hiPSC)-CMs. Compared with conventionally cultured hiPSC-CMs, metabolically matured hiPSC-CMs contract with greater force and show an increased reliance on cardiac sodium (Na) channels and sarcoplasmic reticulum calcium (Ca) cycling. The media enhance the function, long-term survival, and sarcomere structures in engineered heart tissues. Use of the maturation media made it possible to reliably model two genetic cardiac diseases: long QT syndrome type 3 due to a mutation in the cardiac Na channel SCN5A and dilated cardiomyopathy due to a mutation in the RNA splicing factor RBM20. The maturation media should increase the fidelity of hiPSC-CMs as disease models.
诱导多能干细胞衍生的心肌细胞（iPSC-CMs）在研究人类心脏疾病方面具有巨大的潜力。然而，其生理不成熟严重限制了它们作为模型系统的实用性，也限制了它们在药物发现中的应用。在这里，我们描述了旨在提供适应人类 iPSC（hiPSC）-CM 代谢需求的氧化底物的成熟培养基。与传统培养的 hiPSC-CMs 相比，代谢成熟的 hiPSC-CMs 收缩力更强，对心脏钠离子（Na）通道和肌浆网钙（Ca）循环的依赖性增加。该培养基增强了工程心脏组织中的功能、长期存活和肌节结构。使用成熟培养基，可以可靠地模拟两种遗传性心脏病：由心脏 Na 通道 SCN5A 突变引起的长 QT 综合征 3 型和由 RNA 剪接因子 RBM20 突变引起的扩张型心肌病。成熟培养基应提高 hiPSC-CMs 作为疾病模型的准确性。
