Direct hydrogel encapsulation of pluripotent stem cells enables ontomimetic differentiation and growth of engineered human heart tissues.
Direct hydrogel encapsulation of pluripotent stem cells enables ontomimetic differentiation and growth of engineered human heart tissues.
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DOI：
10.1016/j.biomaterials.2015.12.011
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发表时间：
2016-03
期刊：
影响因子：
14
通讯作者：
Lipke EA
中科院分区：
文献类型：
--
作者：
Kerscher P;Turnbull IC;Hodge AJ;Kim J;Seliktar D;Easley CJ;Costa KD;Lipke EA
人类工程心脏组织有可能彻底改变心脏发育研究、药物测试和心脏病的治疗；然而，由于需要使用预分化心肌细胞（CM），实施受到限制。在这里，我们表明，通过提供 3D 聚乙二醇-纤维蛋白原水凝胶微环境，我们可以直接将人类多能干细胞 (hPSC) 分化为收缩的心脏组织。我们直接的、本体模拟的方法模仿发育过程，只需要一个细胞处理步骤，为一系列测试的几何形状和尺寸尺度提供可重复的结果，并克服细胞维持和成熟的固有限制，同时实现具有适合发育的基因表达时间变化的CM的高产量。在这里，我们证明封装在这种仿生 3D 水凝胶微环境中的 hPSC 发育成由自对准 CM 组成的功能性心脏组织，具有超微结构成熟的证据，模仿心脏发育，并能够研究疾病机制和筛选发育中的人类心脏组织的化合物。
Human engineered heart tissues have potential to revolutionize cardiac development research, drug-testing, and treatment of heart disease; however, implementation is limited by the need to use pre-differentiated cardiomyocytes (CMs). Here we show that by providing a 3D poly(ethylene glycol)-fibrinogen hydrogel microenvironment, we can directly differentiate human pluripotent stem cells (hPSCs) into contracting heart tissues. Our straight-forward, ontomimetic approach, imitating the process of development, requires only a single cell-handling step, provides reproducible results for a range of tested geometries and size scales, and overcomes inherent limitations in cell maintenance and maturation, while achieving high yields of CMs with developmentally appropriate temporal changes in gene expression. Here we demonstrate that hPSCs encapsulated within this biomimetic 3D hydrogel microenvironment develop into functional cardiac tissues composed of self-aligned CMs with evidence of ultrastructural maturation, mimicking heart development, and enabling investigation of disease mechanisms and screening of compounds on developing human heart tissue.