Human embryonic stem cell-derived cardiomyocyte therapy in mouse permanent ischemia and ischemia-reperfusion models
Human embryonic stem cell-derived cardiomyocyte therapy in mouse permanent ischemia and ischemia-reperfusion models
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人胚胎干细胞源性心肌细胞治疗小鼠永久性缺血和缺血再灌注模型
DOI：
10.1186/s13287-019-1271-4
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发表时间：
2019
影响因子：
7.5
通讯作者：
Hu Shijun
中科院分区：
文献类型：
--
作者：
Yu You;Qin Nianci;Lu Xing Ai;Li Jingjing;Han Xinglong;Ni Xuan;Ye Lingqun;Shen Zhenya;Chen Weiqian;Zhao Zhen Ao;Lei Wei;Hu Shijun
背景缺血性心脏病仍然是威胁人类健康的一个重要疾病。基于人多能干细胞的移植在心血管疾病（包括心脏缺血）的治疗中显示出巨大的前景。本研究旨在比较人胚胎干细胞衍生的心肌细胞（ESC-CM）对永久性缺血（PI）和心肌缺血再灌注（IR）两种心肌缺血模型的治疗效果。方法将携带绿色荧光蛋白（GFP）的工程化人胚胎干细胞（ESC-Rep）分化为人胚胎干细胞衍生的心肌细胞，单纯疱疹病毒-1胸苷激酶（HSVtk）和萤火虫荧光素酶（Fluc）。通过结扎左前降支（LAD）建立两种不同的心肌缺血模型，并将ESC-Rep-CMs移植到小鼠心脏中。通过心功能分析评价ESC-Rep-CM移植的结局。进行生物发光信号分析以评估细胞植入。最后，炎症反应进行了分析，通过实时PCR和ELISA.ResultsCardiac功能得到显着改善，在PI组与ESC-Rep-CM注射相比，PBS注射控制，增加左心室射血分数（LVEF）和左心室缩短分数（LVFS），以及减少纤维化面积。然而，在IR小鼠模型中检测到ESC-Rep-CM注射的最小改善。我们在ESC-Rep-CM注射后观察到PI和IR组之间相似的植入效率。PI组注射ESC-Rep-CMs后出现局限性炎症反应，而IR组则无。移植ESC-Rep-CMs可以通过调节PI模型中的炎症反应来部分地保护心脏功能，而IR模型中心脏功能的改善不大，这可能是由于轻度心脏损伤导致的动态炎症反应较少。
BackgroundIschemic 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).MethodsHuman 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.ResultsCardiac 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.ConclusionsOur findings identified the anti-inflammatory effect of ESC-CMs as a possible therapeutic mechanism to improve cardiac function in the ischemic heart.