Robust T-tubulation and maturation of cardiomyocytes using tissue-engineered epicardial mimetics.
Robust T-tubulation and maturation of cardiomyocytes using tissue-engineered epicardial mimetics.
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DOI：
10.1016/j.biomaterials.2014.01.045
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发表时间：
2014-04
期刊：
影响因子：
14
通讯作者：
Bursac, Nenad
中科院分区：
文献类型：
--
作者：
Bian, Weining;Badie, Nima;Himel, Herman D.;Bursac, Nenad
复杂的心脏三维结构是心脏电和机械功能的重要决定因素。在这项研究中，我们着手开发一种通用的组织工程系统，该系统可以促进心脏功能成熟的重要方面，并复制存在于自然心外膜的肌纤维方向的变异。我们在三维水凝胶环境中使用带有六角柱的微型制造的弹性模具来培养新生大鼠心肌细胞。通过沿着人体心室扩散张量磁共振成像(DTMRI)图得出的方向改变个体的定位，我们创建了具有心肌细胞排列的大型(2.5×2.5 cm2)3-D心脏组织贴片，复制了人类心外膜纤维的定位。培养3周后，与年龄匹配的2-D单层相比，工程化三维心肌组织的结构和功能成熟明显：1)存在致密、排列和机电耦合的心肌细胞、静止的成纤维细胞和散布的毛细血管样结构；2)动作电位以接近成人的传导速度和局部心肌细胞的方向依赖；3)T管与Z盘排列牢固，L型钙通道和兰诺定受体共存，加速钙瞬变动力学。这一仿生组织工程平台可以实现对心脏结构-功能关系的系统体外研究，并促进先进的组织工程策略的发展，用于心脏修复和再生。
Complex three-dimensional (3-D) heart structure is an important determinant of cardiac electrical and mechanical function. In this study, we set to develop a versatile tissue-engineered system that can promote important aspects of cardiac functional maturation and reproduce variations in myofiber directions present in native ventricular epicardium. We cultured neonatal rat cardiomyocytes within a 3-D hydrogel environment using microfabricated elastomeric molds with hexagonal posts. By varying individual post orientations along the directions derived from diffusion tensor magnetic resonance imaging (DTMRI) maps of human ventricle, we created large (2.5 × 2.5 cm2) 3-D cardiac tissue patches with cardiomyocyte alignment that replicated human epicardial fiber orientations. After 3 weeks of culture, the advanced structural and functional maturation of the engineered 3-D cardiac tissues compared to age-matched 2-D monolayers was evident from: 1) the presence of dense, aligned and electromechanically-coupled cardiomyocytes, quiescent fibroblasts, and interspersed capillary-like structures, 2) action potential propagation with near-adult conduction velocity and directional dependence on local cardiomyocyte orientation, and 3) robust formation of T-tubules aligned with Z-disks, co-localization of L-type Ca2+ channels and ryanodine receptors, and accelerated Ca2+ transient kinetics. This biomimetic tissue-engineered platform can enable systematic in vitro studies of cardiac structure-function relationships and promote the development of advanced tissue engineering strategies for cardiac repair and regeneration.
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