Lack of remuscularization following transplantation of human embryonic stem cell-derived cardiovascular progenitor cells in infarcted nonhuman primates
Lack of remuscularization following transplantation of human embryonic stem cell-derived cardiovascular progenitor cells in infarcted nonhuman primates
复制标题
将人胚胎干细胞来源的心血管祖细胞移植到梗塞的非人灵长类动物后缺乏再肌化
DOI：
10.1161/circresaha.117.311578
复制
发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Zhang Jiany
中科院分区：
文献类型：
--
作者：
Zhu Keyang;Wu Qiang;Ni Cheng;Zhang Peng;Zhong Zhiwei;Wu Yan;Wang Yingchao;Xu Yinchuan;Kong Minjian;Cheng Haifeng;Tao Zhihua;Yang Qian;Liang He;Jiang Yun;Li Qingju;Zhao Jing;Huang Jijun;Zhang Fengjiang;Chen Qi;Li Yi;Chen Jinghai;Zhu Wei;Yu Hong;Zhang Jiany
目的：本研究的主要目的是阐明心肌梗死（MI）后hPSC-CVPC能否在灵长类动物心脏内长期移植，并比较单用环孢素或含环孢素、甲泼尼龙和巴利昔单抗的多药方案（MDR）对MI后接受1× 107 EGFP（增强型绿色荧光蛋白）表达的食蟹猴进行免疫抑制的有效性和安全性。方法与结果：EGFP基因表达和EGFP免疫荧光染色结果显示，MI+MDR+CVPC组的hPSC-CVPC植入率高于MI+环孢素+CVPC组。然而，即使在MI+MDR+CVPC组中，在移植后140天也不能检测到移植细胞。同时，CD 3，CD 4和CD 8表达的免疫荧光分析表明，在CVPC移植的心脏T淋巴细胞浸润是在MDR治疗的动物比环孢素单独治疗的动物。MI+MDR+CVPC组心肌梗死后28 d左心功能恢复优于MI+MDR组。心肌细胞凋亡也不常见的MI+MDR+CVPC组比MI+MDR组，虽然这两种免疫抑制方案与短暂的肝功能dysfunctions.Conclusions：这是最大的研究hPSC在非人灵长类动物在心血管领域的日期（n=32）。与单独的环孢素相比，MDR减弱了免疫排斥反应并改善了灵长类动物中hPSC-CVPC的存活率;这与天然心脏细胞的凋亡较少和28天时左心室功能的恢复更好有关。然而，即使有MDR，移植的hPSC-CVPC也不移植，并且在移植后140天不存活，从而排除了作为功能效应机制的肌再生。
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 1×107EGFP (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.