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Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitor Cells Improves Cardiac Function without Remuscularization in Infarcted Nonhuman Primates

Feb 02, 2018     Email"> PrintText Size

Myocardial infarction (MI) is the leading cause of morbidity and mortality worldwide. Human pluripotent stem cells (hPSCs)-derived cardiovascular progenitor cells (CVPCs) hold great promise for the myocardial repair of MI.

Before clinical trials, preclinical studies in large-animal models are necessary to characterize the efficacy and safety of hPSC-CVPCs. Immune rejection is one of the major barriers to the successful completion of xenogeneic transplantation studies, especially when conducted in nonhuman primates.

Recently, Dr. YANG Huangtian’s group at Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences collaborating with researchers at the Second Affiliated Hospital of Zhejiang University compared cyclosporine alone with a combination of cyclosporine, methylprednisolone, and the CD25 antibody Simulect (multiple-drug regimen [MDR]) in cynomolgous monkeys that were transplanted with hPSC-CVPCs into myocardium with experimentally induced acute MI.

The researchers found that compared to cyclosporine alone, MDR attenuates immune rejection and improves survival of hPSC-CVPCs in primates with acute MI, which is associated with less apoptosis of native cardiac cells at three days post-MI and better recovery of left ventricular function at 28 days post-MI, evidenced by TUNEL staining and echocardiographic assessments.

However, even with MDR, as quantitative RT-PCR and Western blot analysis showed, transplanted hPSC-CVPCs did not engraft and survive at 140 days after transplantation, indicating paracrine effects contribute to the benefits of hPSC-CVPCs but not remuscularization in infarct repair.

Concomitantly, infiltration of nuetrophils, macrophages and T lymphocyte in the border zone of the hPSC-CVPC-transplanted infarcted hearts was found being less in the MDR-treated animals than these in the cyclosporine alone-treated ones, while both immunosuppression regiments are associated with transient hepatic dysfunction.

This was the largest study of hPSCs in non-human primates in cardiovascular field so far (n=32). The findings suggested that cyclosporine regimen does not protect the transplanted cells from immune rejection, but the combination of immune suppressive agents significantly improves the survival of transplanted hPSC-CVPCs via efficiently attenuating immune rejection in the infarcted monkey hearts.

Moreover, although the transplanted cells do not survive for a long term, an improvement of LV function occurs in the combination of immune suppressive agents, indicating that benefits of hPSC-CVPCs is related to their paracrine effects, which provides important understanding for translational research in cardiac repair of infarcted hearts by cell therapy.

The study was published online in Circ Res. It was funded by National Natural Science Foundation of China, Ministry of Science and Technology of China, Chinese Academy of Sciences, etc. 

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(Editor: LIU Jia)

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