Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000, China.
Institute of Microcirculation & Department of Pathophysiology of Basic Medical College, Hebei North University, Zhangjiakou, 075000, Hebei, China.
Stem Cell Res Ther. 2019 Jun 13;10(1):167. doi: 10.1186/s13287-019-1271-4.
Ischemic heart diseases are still a threat to human health. Human pluripotent stem cell-based transplantation exhibits great promise in cardiovascular disease therapy, including heart ischemia. The purpose of this study was to compare the efficacy of human embryonic stem cell-derived cardiomyocyte (ESC-CM) therapy in two heart ischemia models, namely, permanent ischemia (PI) and myocardial ischemia reperfusion (IR).
Human embryonic stem cell-derived cardiomyocytes were differentiated from engineered human embryonic stem cells (ESC-Rep) carrying green fluorescent protein (GFP), herpes simplex virus-1 thymidine kinase (HSVtk), and firefly luciferase (Fluc). Two different heart ischemia models were generated by the ligation of the left anterior descending artery (LAD), and ESC-Rep-derived cardiomyocytes (ESC-Rep-CMs) were transplanted into the mouse hearts. Cardiac function was analyzed to evaluate the outcomes of ESC-Rep-CM transplantation. Bioluminescence signal analysis was performed to assess the cell engraftment. Finally, the inflammation response was analyzed by real-time PCR and ELISA.
Cardiac function was significantly improved in the PI group with ESC-Rep-CM injection compared to the PBS-injected control, as indicated by increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), as well as reduced fibrotic area. However, minimal improvement by ESC-Rep-CM injection was detected in the IR mouse model. We observed similar engraftment efficiency between PI and IR groups after ESC-Rep-CM injection. However, the restricted inflammation was observed after the injection of ESC-Rep-CMs in the PI group, but not in the IR group. Transplantation of ESC-Rep-CMs can partially preserve the heart function via regulating the inflammation response in the PI model, while little improvement of cardiac function in the IR model may be due to the less dynamic inflammation response by the mild heart damage.
Our findings identified the anti-inflammatory effect of ESC-CMs as a possible therapeutic mechanism to improve cardiac function in the ischemic heart.
缺血性心脏病仍然是人类健康的威胁。基于人多能干细胞的移植在心血管疾病治疗中具有巨大的应用前景，包括心脏缺血。本研究旨在比较人胚胎干细胞衍生的心肌细胞（ESC-CM）在两种心脏缺血模型（即永久性缺血（PI）和心肌缺血再灌注（IR））中的疗效。
从携带绿色荧光蛋白（GFP）、单纯疱疹病毒-1 胸苷激酶（HSVtk）和萤火虫荧光素酶（Fluc）的工程化人胚胎干细胞（ESC-Rep）中分化出人胚胎干细胞衍生的心肌细胞（ESC-Rep-CMs）。通过结扎左前降支（LAD）生成两种不同的心脏缺血模型，并将 ESC-Rep 衍生的心肌细胞（ESC-Rep-CMs）移植到小鼠心脏中。通过分析心脏功能来评估 ESC-Rep-CM 移植的结果。通过生物发光信号分析来评估细胞移植情况。最后，通过实时 PCR 和 ELISA 分析炎症反应。
与 PBS 注射对照组相比，ESC-Rep-CM 注射可显著改善 PI 组的心脏功能，表现为左心室射血分数（LVEF）和左心室缩短分数（LVFS）增加，纤维化面积减少。然而，在 IR 小鼠模型中，ESC-Rep-CM 注射的改善作用较小。ESC-Rep-CM 注射后，PI 组和 IR 组的细胞移植效率相似。然而，在 PI 组中观察到 ESC-Rep-CMs 注射后的限制炎症，而在 IR 组中则没有。ESC-Rep-CMs 的移植可以通过调节 PI 模型中的炎症反应来部分维持心脏功能，而在 IR 模型中对心脏功能的改善较小可能是由于轻度心脏损伤导致的炎症反应不那么活跃。
我们的研究结果确定了 ESC-CMs 的抗炎作用是改善缺血性心脏功能的一种可能的治疗机制。
