Impact of Cell Composition and Geometry on Human Induced Pluripotent Stem Cells-Derived Engineered Cardiac Tissue.
Impact of Cell Composition and Geometry on Human Induced Pluripotent Stem Cells-Derived Engineered Cardiac Tissue.
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DOI：
10.1038/srep45641
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发表时间：
2017-04-03
影响因子：
4.6
通讯作者：
Keller BB
中科院分区：
文献类型：
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作者：
Nakane T;Masumoto H;Tinney JP;Yuan F;Kowalski WJ;Ye F;LeBlanc AJ;Sakata R;Yamashita JK;Keller BB
目前的研究描述了一种可扩展、多孔的大型工程心脏组织 (LF-ECT)，由人类诱导多能干细胞 (hiPSC) 衍生的多谱系心脏细胞组成，具有不同的 3D 几何形状和细胞密度，旨在实现大型动物临床前研究规模化的目标。我们使用具有矩形内部交错柱（网状，ME）、无柱（普通片，PS）或长平行柱（多个线性束，ML）的模具以及含有在体外成熟14天的hiPSC衍生的心肌细胞、内皮细胞和血管壁细胞的凝胶基质，探索了多个15 × 15 mm ECT几何形状。 ME-ECT 显示出最低的死细胞比率 (p<0.001)，并成熟为 0.5 毫米直径的肌纤维束，与 PS-ECT 相比，具有更好的 3D 细胞排列和更高的主动应力。每个构建体的初始 ECT 细胞数量超过 6 M，导致细胞存活率降低和主动应激降低。将 6M-ME-ECT 植入梗死后 1 周的免疫耐受大鼠心脏，显示出宿主血管耦合的证据，并恢复了心肌结构和功能，并减少了疤痕面积。我们生成了一个更大的（30 × 30 mm）ME-ECT 来确认可扩展性。因此，由 hiPSC 衍生的心脏细胞产生的大幅面 ECT 对于大型动物临床前心脏再生范例可能是可行的。
The current study describes a scalable, porous large-format engineered cardiac tissue (LF-ECT) composed of human induced pluripotent stem cells (hiPSCs) derived multiple lineage cardiac cells with varied 3D geometries and cell densities developed towards the goal of scale-up for large animal pre-clinical studies. We explored multiple 15 × 15 mm ECT geometries using molds with rectangular internal staggered posts (mesh, ME), without posts (plain sheet, PS), or long parallel posts (multiple linear bundles, ML) and a gel matrix containing hiPSC-derived cardiomyocytes, endothelial, and vascular mural cells matured in vitro for 14 days. ME-ECTs displayed the lowest dead cell ratio (p < 0.001) and matured into 0.5 mm diameter myofiber bundles with greater 3D cell alignment and higher active stress than PS-ECTs. Increased initial ECT cell number beyond 6 M per construct resulted in reduced cell survival and lower active stress. The 6M-ME-ECTs implanted onto 1 week post-infarct immune tolerant rat hearts engrafted, displayed evidence for host vascular coupling, and recovered myocardial structure and function with reduced scar area. We generated a larger (30 × 30 mm) ME-ECT to confirm scalability. Thus, large-format ECTs generated from hiPSC-derived cardiac cells may be feasible for large animal preclinical cardiac regeneration paradigms.