Human Engineered Heart Muscles Engraft and Survive Long Term in a Rodent Myocardial Infarction Model.
Human Engineered Heart Muscles Engraft and Survive Long Term in a Rodent Myocardial Infarction Model.
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DOI：
10.1161/circresaha.115.306985
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发表时间：
2015-09-25
影响因子：
20.1
通讯作者：
Wu JC
中科院分区：
文献类型：
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作者：
Riegler J;Tiburcy M;Ebert A;Tzatzalos E;Raaz U;Abilez OJ;Shen Q;Kooreman NG;Neofytou E;Chen VC;Wang M;Meyer T;Tsao PS;Connolly AJ;Couture LA;Gold JD;Zimmermann WH;Wu JC
组织工程方法可以提高人胚胎干细胞衍生的心肌细胞（ESC-CM）移植的存活率和功能益处，从而可能防止扩张性重塑和进展为心力衰竭。在慢性心肌梗死（MI）模型中评估工程化心肌（EHM）的运输稳定性、长期存活率、结构组织、功能益处和畸胎瘤风险。我们从ESC-CM构建了EHM，并按照预定义的质量控制标准将其发布用于跨大西洋运输。运输两天未对EHM的细胞活力或收缩性能产生不良影响（n=3，P=0.83，P=0.87）。在缺血/再灌注（I/R）损伤后，将EHM植入免疫受损的大鼠心脏1个月以模拟慢性缺血。生物发光成像（BLI）显示稳定的植入，在第2周和第12周之间没有显著的细胞损失（n=6，P=0.67），保留了高达25%的移植细胞。尽管移植率高，疾病进展减缓（EHM射血分数变化为−6.7±1.4% vs对照组−10.9± 1.5%，n>12，P=0.05），但我们观察到在这种慢性异种移植模型中，含有存活或非存活人类心肌细胞的EHM之间没有差异（n>12，P=0.41）。移植的心肌细胞在移植后220天显示增强的肌节排列和增加的连接蛋白43表达。在用于长期监测的任何动物（n=14）中均未发现畸胎瘤或肿瘤。EHM移植导致高植入率、长期存活和人心肌细胞的逐渐成熟。然而，在这种慢性MI模型中，细胞植入与功能改善无关。最重要的是，这种方法的安全性是通过没有肿瘤或畸胎瘤形成来证明的。
Tissue engineering approaches may improve survival and functional benefits from human embryonic stem cell-derived cardiomyocte (ESC-CM) transplantation, thereby potentially preventing dilative remodelling and progression to heart failure. Assessment of transport stability, long term survival, structural organisation, functional benefits, and teratoma risk of engineered heart muscle (EHM) in a chronic myocardial infarction (MI) model. We constructed EHMs from ESC-CMs and released them for transatlantic shipping following predefined quality control criteria. Two days of shipment did not lead to adverse effects on cell viability or contractile performance of EHMs (n=3, P=0.83, P=0.87). After ischemia/reperfusion (I/R) injury, EHMs were implanted onto immunocompromised rat hearts at 1 month to simulate chronic ischemia. Bioluminescence imaging (BLI) showed stable engraftment with no significant cell loss between week 2 and 12 (n=6, P=0.67), preserving up to 25% of the transplanted cells. Despite high engraftment rates and attenuated disease progression (change in ejection fraction for EHMs −6.7±1.4% vs control −10.9±1.5%, n>12, P=0.05), we observed no difference between EHMs containing viable or non-viable human cardiomyocytes in this chronic xenotransplantation model (n>12, P=0.41). Grafted cardiomyocytes showed enhanced sarcomere alignment and increased connexin 43 expression at 220 days after transplantation. No teratomas or tumors were found in any of the animals (n=14) used for long-term monitoring. EHM transplantation led to high engraftment rates, long term survival, and progressive maturation of human cardiomyocytes. However, cell engraftment was not correlated with functional improvements in this chronic MI model. Most importantly, the safety of this approach was demonstrated by the lack of tumor or teratoma formation.