Stem cells regenerate damaged monkey heart

Donor’s cells integrated with no sign of rejection to regenerate recipient’s heart.

Today’s Nature study reveals that cardiac muscle cells grown from the stem cells of one macaque monkey can be used to regenerate the hearts of other macaques. The transplanted cells improved the heart’s ability to contract after an induced heart attack and integrated with no sign of rejection by the recipient’s immune system. However, the recipient’s heart did suffer from an irregular heart beat in the first four weeks after the transplant, but this passed and was non-lethal.

Yuji Shiba, Shinshu University, Matsumoto, Japan and colleagues used cardiac muscle cells derived from induced pluripotent stem cells (iPSC-CMs) from a donor instead of the patient’s own cells. Donor cells are considerably easier to manufacture but increase the risk of being rejected by the recipient’s immune systems. Shiba overcame this by matching a surface protein on the donor and recipient’s cells that is used by the immune system to recognize foreign cells.

We spoke to Yuji Shiba.

ResearchGate: What motivated this study?

Yuji Shiba: We previously reported that human embryonic stem cells regenerated injured guinea pig hearts when I worked at the University of Washington as a post-doctoral fellow. I came back to Japan in 2011 and wanted to start something a bit different.

RG: What were the results?

Shiba: We found that monkey iPSC-CMs or cardiac muscle cells derived from induced pluripotent stem cells survived in the damaged monkey heart and electrically coupled with the host heart. In addition, the heart’s ability to contract was partially recovered by the transplantation.

RG: What heart conditions could this treat?

Shiba: We blocked oxygen from the heart for three hours which caused myocardial infarction (MI). The heart also suffered from reperfusion, which is tissue damage caused by the blood and oxygen returning to the heart. The induced pluripotent stem cells (iPSC-CMs) were transplanted two weeks after the induction of MI.

So far, we only have evidence that an acutely or sub-acutely infarcted heart was rescued by this treatment, but in a clinical setting, patients with chronic infarction would be more likely to receive this treatment.

iPS cells were generated from MHC homozygous monkey and differentiated into cardiomyocytes. The cardiomyocytes were transplanted into another monkey in which either of the MHC haplotypes was identical to the donor. Credit: Yuji Shiba
iPS cells were generated from MHC homozygous monkey and differentiated into cardiomyocytes. The cardiomyocytes were transplanted into another monkey in which either of the MHC haplotypes was identical to the donor. Credit: Yuji Shiba

RG: Were you confident that this would work when you started? What were the biggest challenges in the study?

Shiba: To some extent, yes. We had a hard time handling monkey iPS cells. Unlike human iPS cells, they are somewhat tricky. The condition of iPS cells are critical for generating high purity cardiac muscle cells. Also, it took a long time to get grafted cardiac muscle cells to survive in the recipients.

RG: How did you avoid an immune response from the recipient when using a donor’s cells?

Shiba: In addition to daily treatments of the immunosuppressant drugs methylprednisolone and tacrolimus, we made sure the surface protein MHC, which is used by the immune system to recognize foreign cells, was carefully matched on the donor and recipient’s cells.

RG: What negative side effects did you encounter? Can these be overcome?

Shiba: Ventricular arrhythmia was induced by the transplantation, typically within the first four weeks. However, this post-transplant arrhythmia seems to be transient and non-lethal. All five recipients of iPSC-CMs survived without any abnormal behavior for 12 weeks, even during the arrhythmia. So I think we can manage this side effect in clinic.

RG: How long before we could see this in human clinical trials?

Shiba: Human embryonic stem cell-derived cardiac muscle cells have already been used in clinic as a new therapy for post myocardial infarction (MI) heart failure. But I think it will take at least a couple of years for this treatment to become more widely-used.

RG: What excites you most about the future of stem cell therapy?

Shiba: Our ultimate goal is to provide autologous, meaning the cells are the patient’s own, patient specific cardiac muscle cells to cure not only myocardial infarction (MI) but any kind of heart disease.

Featured image courtesy of Trey Ratcliffe.