Lack of Remuscularization Following Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitor Cells in Infarcted Nonhuman Primates. Issue 7 (30th March 2018)

• Record Type: Journal Article
• Authors: 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, Jianyi; Yang, Huang-Tian; Hu, Xinyang; Wang, Jian'an
• Is Part Of: Circulation research. Volume 122:Issue 7(2018)
• Publication Date: 2018-03-30
• Subjects: human embryonic stem cells -- immunosuppression -- primates -- transplantation; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.117.311578
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : 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 1×10 7 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. Abstract : Supplemental Digital Content is available in the text.