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Lack of Remuscularization Following Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitor Cells in Infarcted Nonhuman PrimatesNovelty and Significance
Circulation Research ( IF 20.1 ) Pub Date : 2018-03-30 , DOI: 10.1161/circresaha.117.311578
Keyang Zhu 1 , Qiang Wu 1 , Cheng Ni 1 , Peng Zhang 1 , Zhiwei Zhong 1 , Yan Wu 1 , Yingchao Wang 1 , Yinchuan Xu 1 , Minjian Kong 1 , Haifeng Cheng 1 , Zhihua Tao 1 , Qian Yang 1 , He Liang 1 , Yun Jiang 1 , Qingju Li 1 , Jing Zhao 1 , Jijun Huang 1 , Fengjiang Zhang 1 , Qi Chen 1 , Yi Li 1 , Jinghai Chen 1 , Wei Zhu 1 , Hong Yu 1 , Jianyi Zhang 1 , Huang-Tian Yang 1 , Xinyang Hu 1 , Jian’an Wang 1
Affiliation  

Rationale: Human pluripotent stem cell–derived cardiovascular progenitor cells (hPSC-CVPCs) should be thoroughly investigated in large animal studies before testing in clinical trials.
Objective: The main of this study is to clarify whether hPSC-CVPCs can engraft for long time in the heart of primates after myocardial infarction (MI) and compare the effectiveness and safety of immunosuppression with cyclosporine alone or multiple-drug regimen (MDR) containing cyclosporine, methylprednisolone, and basiliximab in cynomolgus monkeys that had received intramyocardial injections of 1×107 EGFP (enhanced green fluorescent protein)-expressing hPSC-CVPCs after MI. A third group of animals received the immunosuppression MDR but without cell therapy after MI (MI+MDR group).
Methods and Results: Measurements of EGFP gene levels and EGFP immunofluorescence staining indicated that the hPSC-CVPC engraftment rate was greater in the MI+MDR+CVPC group than that in the MI+cyclosporine+CVPC group. However, even in the MI+MDR+CVPC group, no transplanted cells could be detected at 140 days after transplantation. Concomitantly, immunofluorescent analysis of CD3, CD4, and CD8 expression indicated that T-lymphocyte infiltration in the CVPC-transplanted hearts was less in the MDR-treated animals than in the cyclosporine-alone–treated animals. The recovery of left ventricular function on day 28 post-MI in the MI+MDR+CVPC group was better than that in the MI+MDR group. Apoptotic cardiac cells were also less common in the MI+MDR+CVPC group than in the MI+MDR group, although both immunosuppression regimens were associated with transient hepatic dysfunction.
Conclusions: This is the largest study of hPSCs in nonhuman primates in cardiovascular field to date (n=32). Compared with cyclosporine alone, MDR attenuates immune rejection and improves survival of hPSC-CVPCs in primates; this is associated with less apoptosis of native cardiac cells and better recovery of left ventricular function at 28 days. However, even with MDR, transplanted hPSC-CVPCs do not engraft and do not survive at 140 days after transplantation, thereby excluding remuscularization as a mechanism for the functional effect.


中文翻译:

人胚性干细胞衍生的心血管祖细胞移植在梗死的非人灵长类动物中的缺乏肌肉再生的新颖性和意义

理由:在人类动物多能干细胞源性心血管祖细胞(hPSC-CVPCs)之前,应在大型动物研究中进行彻底研究,然后再进行临床试验测试。
目的:本研究的主要目的是弄清hPSC-CVPCs是否可以在心肌梗死(MI)后长时间植入灵长类动物心脏,并比较单独使用环孢素或多药方案(MDR)进行免疫抑制的有效性和安全性心肌梗死后接受心肌内注射表达1×10 7 EGFP(增强型绿色荧光蛋白)的hPSC-CVPC的食蟹猕猴中的环孢素,甲基强的松龙和巴利昔单抗。第三组动物在MI后接受了免疫抑制MDR,但未进行细胞治疗(MI + MDR组)。
方法和结果:EGFP基因水平和EGFP免疫荧光染色的测量表明,MI + MDR + CVPC组的hPSC-CVPC植入率高于MI +环孢菌素+ CVPC组。但是,即使在MI + MDR + CVPC组中,在移植后140天也未检测到移植细胞。同时,对CD3,CD4和CD8表达的免疫荧光分析表明,经CVPC移植的心脏中,接受MDR治疗的动物的T淋巴细胞浸润少于单独使用环孢霉素的动物。MI + MDR + CVPC组在MI后第28天左心室功能的恢复要好于MI + MDR组。MI + MDR + CVPC组的凋亡性心肌细胞也比MI + MDR组的少,
结论:这是迄今为止心血管领域非人类灵长类动物中最大的hPSCs研究(n = 32)。与单独使用环孢菌素相比,MDR可减轻灵长类动物的免疫排斥反应并提高hPSC-CVPC的存活率;这与28天天然心肌细胞的凋亡减少和左心室功能恢复更好有关。但是,即使使用MDR,移植的hPSC-CVPC也不会移植,并且在移植后140天不能存活,因此排除了将肌再生作为功能作用机制的可能性。
更新日期:2018-03-30
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