Author + information
- Keyang Zhu1,3,
- Qiang Wu2,6,
- Cheng Ni1,3,
- Peng Zhang2,6,
- Zhiwei Zhong1,3,
- Yan Wu1,3,
- Yingchao Wang1,3,
- Yinchuan Xu1,3,
- Minjian Kong4,
- Haifeng Cheng4,
- Fengjiang Zhang5,
- Qi Chen5,
- Yi Li5,
- Yun Jiang2,6,
- Jianyi Zhang7,
- Huangtian Yang2,
- Xinyang Hu1,3 and
- Jianan Wang1,3
- 1Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University
- 2Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences
- 3Cardiovascular Key Laboratory of Zhejiang Province
- 4Department of Cardiovascular Surgery, Second Affiliated Hospital, College of Medicine, Zhejiang University
- 5Department of Anesthesiology, Second Affiliated Hospital, College of Medicine, Zhejiang University
- 6University of Chinese Academy of sciences
- 7Department of Biomedical Engineering, University of Alabama
Human pluripotent stem cell-derived cardiac lineage cells hold great promise for cardiac repair following injury. The evaluation of their therapeutic properties for both efficiency and safety in large animal studies are prerequisite for clinic applications. However, immune rejection is one of the major barriers in preclinical xenotransplantation animal study, especially in nonhuman primates. To determine suitable immunosuppression strategies for human pluripotent stem cell-derived cardiac lineage cells in nonhuman primates.
We compared immunosuppression efficiency and safety of a combination strategy using cyclosporine, methylprednisolone and simulect (cocktail group) with cyclosporine alone (cyclosporine group) in cynomolgus monkeys subject to myocardial infarction (MI) with or without cell transplantation. MI was established in thirteen cynomolgus monkeys with permanent ligation of left anterior-descending coronary artery following by direct intra-myocardial injection of H9-EGFPhuman embryonic stem cell-derived cardiovascular progenitor cells (ESC-CVPCs) or cell solution as non-cell control.
The cocktail group significantly improved the engraftment rate of transplanted cells and decreased the number of CD3+,CD4+,CD8+ T lymphocytes in the border zone compared with the cyclosporine group at day 3 after transplantation, while the transplanted cells could not be detected either by GFP immunofluorescence staining or QPCR analysis at 20 weeks. More engraftment rate of transplanted cells was associated with reduced apoptotic cells observed in cocktail group compared with that in the cyclosporine group and MI group, but no difference between the cyclosporine group and MI group. Notably, Immune suppression agents in both group caused hepatic dysfunction during use of immunosuppress agents.
The immunosuppression cocktail sufficiently attenuates immune rejection and improves the engraftment of hESC-CVPCs in nonhuman primates compared with cyclosporine alone but both strategies cause the hepatic injury.