Combining cell types may lead to improved cardiac cell therapy following a myocardial infarction

Researchers at the University of Wisconsin–Madison and Academia Sinica, Taiwan, have identified a novel strategy that harnesses a combination of lab-grown cells to regenerate damaged heart muscle, marking a noteworthy advancement in cardiac regeneration research. The study published in Circulation addresses major challenges associated with using induced pluripotent stem cell (iPSC)-derived cardiomyocytes for cardiac cell transplantation therapy which is a crucial step toward future clinical applications.

While previous studies have shown that the remuscularization of the mammalian heart can be achieved using cell transplantation of human pluripotent stem cell–derived cardiomyocytes, also known as heart muscle cells, researchers have struggled to bring this to the clinic as poor survival of the implanted cells in the failing heart has hindered its implementation as a therapy. This study confronted that challenge by demonstrating that iPSC–derived cardiomyocytes are more likely to survive and thrive when combined in co-transplantation with iPSC-derived endothelial cells, which are the cells that line blood vessels. The combination therapy also holds promise for tackling arrhythmia, another significant obstacle in iPSC-derived cardiomyocyte-based heart regeneration.

“Our findings suggest that human iPSC-derived endothelial cells can effectively augment the remuscularization of the heart by iPSC-derived cardiomyocytes, offering a promising avenue for future clinical applications,” says Patrick Hsieh, a researcher with the Institute of Biomedical Sciences, Academia Sinica, Taiwan, who conducted the study while working as a visiting professor at the UW–Madison Stem Cell & Regenerative Medicine Center (SCRMC).

Human heart cells (shown in the lower half with green color and red stripes, Z-lines) engrafted in a nonhuman primate heart with native heart cells (shown with red stripes without green). Image courtesy of Yu-Che Cheng

To demonstrate these findings, Hsieh and lead author Yu-Che Cheng, collaborated with Tim Kamp, who serves as director of SCRMC, as well as a team of researchers at UW-Madison and the Wisconsin National Primate Research Center, to examine the therapeutic effect of co-transplantation in mice and non-human primates undergoing myocardial infarction (a heart attack).

“The main advantage of iPSCs is their ability to be differentiated into many types of cells and serve as a valuable resource for cell therapy,” says Cheng, who is a project manager at Academia Sinica. “In this study, we generated billions of endothelial cells and cardiomyocytes from the same iPSCs line to inject into mice and non-human primates. To achieve it, we had to have well-established protocol for cell differentiation and characterization. More importantly, great teamwork in the group is indispensable for this accomplishment.”

Through these studies, researchers were able to determine that combining iPSC-derived endothelial cells and cardiomyocytes for therapy following a myocardial infarction, or heart attack, leads to enhanced therapeutic potential.

“The impact of this research is substantial,” says Hsieh. “Our findings suggest that human iPSC-derived endothelial cells can effectively augment the remuscularization of the heart by iPSC-derived cardiomyocytes, offering a promising avenue for future clinical applications.”

Kamp added, “The simple idea of the project was to enhance blood flow and promote survival of iPSC-cardiomyocytes using blood vessel forming endothelial cells, but the reality of generating the optimal cell preparations followed by precise delivery to the heart reflects tremendous effort by an international team of collaborators.”

In the future, the team would like to conduct further pre-clinical studies to refine the transplantation protocols and assess long-term safety and efficacy. If these studies continue to show promise, Hsieh believes that they will be able to conduct clinical trials to evaluate the therapeutic potential of this combined iPSC-derived cell therapy in human patients with ischemic heart injury.

“Heart disease remains a leading cause of morbidity and mortality worldwide. Finding innovative and effective therapies that can repair damaged heart tissue, reduce arrhythmia and improve patient outcomes is not only scientifically fascinating but also has the potential to save lives and enhance the quality of life for those affected by heart disease,” says Hsieh. “Personally, as a cardiac surgeon now focusing on translational research, the most exciting aspect of this research is the potential to make a meaningful impact on the treatment of heart disease. Witnessing the significant improvements in cardiac function and tissue regeneration resulting from our combined cell therapy approach is both inspiring and promising for the future of cardiovascular medicine.”

This research was supported by grants from the including Taiwan’s Ministry of Science and Technology, National Health Research Institutes, and the Healthy Longevity Grand Challenge of US National Academy of Medicine and Academia Sinica, along with the NIH, NSF, and the University of Wisconsin Institute for Clinical and Translational Research. We are grateful for the generous support of these organizations, which allowed us to conduct this groundbreaking research and advance our understanding of heart regeneration.