Establishment and Industrialization of a New Treatment Method Using Regenerative Cardiomyocyte Transplantation for
1Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
Insights
Scientists developed a method to generate pure, functional cardiomyocytes from induced pluripotent stem cells (iPSCs). These iPSC-derived cardiomyocytes show promise for treating heart failure by regenerating damaged heart muscle without tumor formation.
Area of Science:
- Regenerative Medicine
- Cardiology
- Stem Cell Biology
Background:
- Cardiomyocytes, the heart muscle cells, do not divide after birth, leading to heart failure upon significant loss.
- Current treatments for heart failure are limited, necessitating novel regenerative approaches.
Purpose of the Study:
- To develop a safe and efficient method for generating purified, functional cardiomyocytes from induced pluripotent stem cells (iPSCs).
- To assess the safety and efficacy of iPSC-derived cardiomyocytes for potential heart failure treatment.
Main Methods:
- Generation of iPSCs from peripheral blood T cells.
- Differentiation of iPSCs into ventricle-specific cardiomyocytes.
- Purification of cardiomyocytes using a metabolic selection method.
- Mass production and transplantation of cardiomyocyte spheroids.
- Preclinical safety and efficacy studies in animal models (mice, rats, pigs, monkeys).
Main Results:
- Achieved >99% purity of human ventricular muscle-specific cardiomyocytes.
- Demonstrated sustained autonomic beating of transplanted cardiomyocytes in mice for over a year without tumor formation.
- Confirmed safety and efficacy through extensive preclinical studies.
Conclusions:
- The developed technology enables the generation of highly pure, functional cardiomyocytes from iPSCs.
- These iPSC-derived cardiomyocytes represent a promising therapeutic strategy for heart failure.
- Future clinical trials aim to use these cells for treating ischemic heart disease and severe heart failure, paving the way for personalized regenerative medicine.
Abstract:
Cardiomyocytes undergo cell division during the fetal period but do not divide after birth; thus, they grow into adult heart cells by enlarging their size. Therefore, heart failure occurs when a certain number of cardiomyocytes are lost owing to myocardial infarction, myocarditis, sarcoidosis, etc. Through scientific efforts, we have developed methods to safely and efficiently generate induced pluripotent stem (iPS) cells from peripheral blood T cells, generate ventricle-specific cardiomyocytes from iPS cells, and remove residual iPS cells and non-cardiomyocytes using the "metabolic selection method" and purify the cardiomyocytes from iPS cell derivatives. We have also developed the technology to mass-produce and efficiently engraft cardiomyocytes by generating cardiomyocyte spheroids and have developed devices suitable for cell transplantation. We have confirmed the safety and efficacy of these techniques by performing preclinical studies (oncogenesis, arrhythmogenicity, etc.) using immunodeficient mice, rats, pigs, and monkeys. Based on these technologies, we have successfully regenerated human ventricular muscle-specific cardiomyocytes with purity greater than 99%. We have also confirmed that the regenerated myocardium transplanted into immunodeficient mice maintained autonomic beating for more than a year without tumor formation. We are planning to conduct clinical trials to transplant iPS cell-derived cardiomyocytes into patients with heart failure associated with ischemic heart disease, which will, in the near future, enable clinical applications using HLA-deficient iPS cells and iPS cells generated from the patient's own lymphocytes to generate regenerative cardiomyocytes without rejection. It would also help establish personalized medicine for heart failure and usher in the long-awaited treatment for intractable severe heart failure using ventricular muscle supplementation.
