iPSC-Derived Cardiomyocytes Taken to Rescue Infarcted Heart Muscle in Coronary Heart Disease Patients
Authors: Seppo Ylä-Herttuala
Journal: Molecular Therapy (2018)

Coronary heart disease is a significant health problem world-wide. In particular, post-infarction heart failure is an increasing problem among elderly patients, even after successful treatment of the primary infarction. Thus, there is a clear need to develop better therapies to improve compromised heart function in a large number of patients. Researchers at Osaka University have recently announced that they will use reprogrammed induced pluripotent stem cells (iPSCs) to generate cardiomyocytes in vitro. The cells are embedded in thin wafer-like sheets and transplanted onto damaged myocardium.1Cyranoski D. ‘Reprogrammed’ stem cells approved to mend human hearts for the first time.Nature. 2018; 557: 619-620Crossref PubMed Scopus (79) Google Scholar Approximately 100 million reprogrammed cardiomyocytes are placed on the ischemic myocardium. According to preclinical experiments in pigs, the treatment is safe and can improve heart function, most likely by the release of several cytokines and growth factors into the damaged heart muscle. In May of this year, Japanese authorities approved treatment of the first three patients using this method. If shown to be safe, investigators will then apply for permission to include 7–10 additional patients in the trial in order to draw conclusions about safety and efficacy of the treatment. However, no randomized controls will be included in the trial. Skeletal muscle and myocardial cell grafting in coronary heart disease and heart failure patients was already tested some years ago in clinical trials, but the outcomes were not successful. Instead, several problems were identified in the early trials: transplanted cells do not engraft into the heart muscle, and therefore cannot improve heart function, and electric coupling of the grafted cells remains problematic and they may even form a focus of dangerous arrhythmias, as has been seen in some previous trials. Grafted cells also need active angiogenesis to provide nutrients and oxygen, which has been difficult to achieve in previous trials. A common outcome has been that the engrafted cells die soon after transplantation. Another open question is whether an optimal set of transcription factors to stimulate the reprogramming process to cardiomyocytes has been identified. Further research in this area is clearly warranted.2Belt H. Koponen J.K. Kekarainen T. Puttonen K.A. Mäkinen P.I. Niskanen H. Oja J. Wirth G. Koistinaho J. Kaikkonen M.U. Ylä-Herttuala S. Temporal Dynamics of Gene Expression During Endothelial Cell Differentiation From Human iPS Cells: A Comparison Study of Signalling Factors and Small Molecules.Front Cardiovasc Med. 2018; 5: 16Crossref PubMed Scopus (6) Google Scholar In the current trial led by cardiac surgeon Yoshiki Sawa, several improvements have been introduced in the treatment protocol: iPSCs are derived from a characterized cell bank, thus improving the overall quality and reproducibility of the starting material so that more standardized cell preparations can be given to the patients, and cells are also grown as thin wafers so they can produce their own extracellular matrix, which avoids the use of foreign biomaterial scaffolds, thereby providing the cells a more natural microenvironment. However, because of the nature of iPSC-derived cardiomyocytes, patients need immunosuppression, which can obviously cause significant side effects. The cell sheets are 0.1 mm thick and 4 cm long. Thus, they can cover large areas of infarcted myocardium, but it remains unclear whether epicardially grafted cell sheets can provide sufficient growth stimulus and regenerative effects in the deeper parts of heart muscle. The trial has also raised ethical concerns, since Japanese regulators allow early testing of new advanced therapeutic approaches without control groups and other additional regulatory hurdles required for phase 1 clinical trials in the US and EU. Obviously, it will be difficult to evaluate a risk/benefit ratio, safety, and efficacy of the new treatment without a randomized control group. Another concerning aspect of the Japanese regulation is that manufacturers can charge patients for the treatment even if there is no proof of efficacy. Despite the above criticism and ethical issues concerning the trial, an iPSC-derived cardiomyocyte clinical trial in coronary heart disease patients is a clear step forward in the use of regenerative medicine approaches for the treatment of human diseases. Methods to bank and differentiate iPSCs in a consistent and reproducible fashion, together with the thin cell sheet technology, should help to better understand biological behavior, cell fate, and the therapeutic potential of redifferentiated cells in humans. Even though the trial is in cardiovascular medicine, results will also be valuable for other areas of iPSC-based regenerative medicine approaches.