While current clinical trials for cardiac regeneration using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) employ immunosuppressive regimens used in heart transplants, the precise immunosuppressive regimen needed remains elusive. Now, researchers have identified optimized immunosuppressive strategies that allow transplanted iPSC-CMs to survive without immune rejection in non-human primates. These findings advance the clinical potential of regenerative therapies for severe heart failure, addressing a major challenge in translating stem cell science into effective human treatments.
Heart failure remains one of the most pressing global health challenges, affecting millions of people and often progressing despite optimal medical care. While heart transplantation can be life-saving, the severe shortage of donor organs and the long-term risks of lifelong immunosuppression significantly limit its usability. Regenerative medicine offers a promising alternative, replacing damaged heart muscle cells with cardiomyocytes derived from induced pluripotent stem cells. However, ensuring that these transplanted cells survive without immune rejection remains a critical barrier to clinical success.
In a new study, a research team led by Assistant Professor Hajime Ichimura and Mr. Shuji Chino from the Division of Cardiovascular Surgery, Department of Surgery, Shinshu University School of Medicine, Japan, along with Dr. Shugo Tohyama from the Fujita Medical Innovation Center Tokyo, Fujita Health University, Japan, and Dr. Shin Kadota and Dr. Yuji Shiba from the Department of Regenerative Science and Medicine, Institute for Biomedical Science, Shinshu University, Japan, set out to clarify how the immune system responds to allogeneic induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) transplantation. Their work specifically examined the efficacy of immunosuppressive regimens commonly used in heart transplantation for stem cell-based cardiac repair. The study was published in Cardiovascular Research on November 18, 2025.
"Current clinical trials for cardiac regeneration using iPSC-CMs employ immunosuppressive regimens similar to those used in heart transplants. However, the optimal and precise level of immunosuppression required after transplantation remains unclear. To unveil this, we explored safer and more effective immunosuppressive regimens for use during iPSC-CM transplantation," says Dr. Ichimura.
The researchers used cynomolgus monkeys, whose immune systems closely resemble those of humans. After inducing myocardial injury, the team transplanted large numbers of allogeneic iPSC-CMs into the hearts of the animals. Different combinations of immunosuppressive drugs were tested, including corticosteroids, methylprednisolone, calcineurin inhibitors, mycophenolate mofetil, and the co-stimulation blocker abatacept. This rigorous experimental approach allowed the researchers to systematically determine which specific drug combinations were sufficient and necessary for graft survival in a primate model.
The results showed that a triple-drug regimen consisting of methylprednisolone, calcineurin inhibitors, and mycophenolate mofetil reliably prevented acute immune rejection of the transplanted cardiomyocytes. When any one of these components was removed, immune cells rapidly rejected the graft, underscoring the need for all three immunosuppressants.
Importantly, the study also explored ways to reduce long-term reliance on steroids, which are associated with serious side effects such as metabolic issues and bone density loss. The researchers found that replacing mycophenolate mofetil with abatacept allowed steroids to be discontinued without triggering immune rejection. This steroid-free approach represents a significant step forward, as it may improve long-term safety and overall quality of life for future patients receiving stem cell-based cardiac therapies.
Beyond immune rejection, the study addressed another major challenge in cardiac cell therapy: post-transplant arrhythmias. Some transplanted cardiomyocytes displayed immature electrical properties, increasing the risk of dangerous heart rhythm disturbances. The team demonstrated that treatment with commonly used antiarrhythmic drugs, amiodarone and ivabradine, dramatically reduced arrhythmia incidence and prevented sudden cardiac death in the primate model.
The broader significance of this research lies in its translational relevance. Clinical trials using iPSC-CMs are already underway, but optimal immunosuppressive strategies have remained unclear. This study provides strong preclinical evidence that carefully tailored immunosuppression is essential for graft survival and that alternative drug combinations may allow safer, steroid-free protocols.
"Our study sheds light on the importance of optimized immunosuppressant regimens for iPSC-CM graft survival. It further highlights the potential improvements in clinical outcomes in patients with severe heart failure. However, further studies are needed to validate these findings and refine immunosuppressive strategies for the widespread clinical use of allogeneic iPSC-CMs in cardiac regeneration," concludes Mr. Chino.
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About Shinshu University
Shinshu University is a national university founded in 1949 and located nestling under the Japanese Alps in Nagano known for its stunning natural landscapes.
Shinshu University was selected for the Forming Japan's Peak Research Universities (J-PEAKS) Program by the Japanese government. This initiative seeks to promote the formation of university consortia that will enhance research capabilities across Japan.
