Unraveling the mystery of reversing myocardial infarction with stem cells


Cardiovascular diseases (CVDs) remain the leading cause of deaths in China. One of the primary reasons for the constantly rising death rate is heart failure due to the loss of cardiomyocytes caused by myocardial infarction (MI). Existing therapies have failed to reverse the process of heart failure.

Therefore, a large body of scientists have endeavored to “resurrect” or “to culture” cardiomyocytes so as to change the seemingly “irrevocable” process. Key to this issue are to reduce the loss of cardiomyocytes and to promote functional restoration, thus inhibiting the development of heart failure and reducing the death rate.

The research team led by WANG Jian’an and HU Xinyang at the Second Affiliated Hospital of ZJU and the team led by HUANG Tian with the Shanghai Institutes for Biological Sciences of the Chinese Academy of Sciences have launched collaborative research into this field. Their research findings reveal the lack of remuscularization following transplantation of human embryonic stem cell-derived cardiovascular progenitor cells (hPSC-CVPCs) in infarcted nonhuman primates. 

Their research aims at clarifying whether hPSC-CVPCs can engraft for a long time in the heart of primates after MI and compare the effectiveness and safety of immunosuppression with cyclosporine alone or multiple-drug regimen (MDR) containing cyclosporine, methylprednisolone, and Simulect in cynomolgous monkeys that have received intramyocardial injections of 1×107 EGFP-expressing hPSC-CVPCs after MI.

In their study, they measured EGFP gene levels and EGFP immunofluorescence staining, indicating 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 140 days after transplantation. Concomitantly, the immunofluorescent analysis of CD3, CD4, and CD8 expression demonstrated 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 (LV) 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, while both immunosuppression regimens were associated with transient hepatic dysfunction.

This has been the largest study of hPSCs in non-human primates in the cardiovascular field so far (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 LV function on 28 days. However, even with MDR, transplanted hPSC-CVPCs do not engraft and do not survive on 140 days after transplantation, thereby excluding remuscularization as a mechanism for the functional effect.

This study provides important data for research into the conversion of stem cells and reveals the pivotal role of the paracrine effect in the protection of hPSC-CVPCs