December 16, 2024
Keio University School of Medicine
Keio University Hospital
University of Tsukuba
A research group led by Professor Masaki Ieda and Assistant Professor Itaro Sadahiro of the Division of Cardiology, Department of Internal Medicine, Keio University School of Medicine, and Assistant Professor Yu Yamada of the Division of Cardiology, Faculty of Medicine, University of Tsukuba, has successfully treated heart failure with preserved ejection fraction using "cardiac direct reprogramming," a form of regenerative medicine that directly induces cardiomyocytes from cardiac fibroblasts.
Cardiomyocytes, which make up the heart, have limited regenerative capacity. The only curative treatment for heart failure with severely reduced cardiac function is heart transplantation, but providing sufficient treatment is difficult due to issues such as donor shortages. Additionally, while regenerative medicine using pluripotent stem cells such as iPS cells has garnered attention, it faces challenges including the risk of tumorigenesis, low tissue engraftment rates and therapeutic efficacy, and a limited therapeutic effect on cardiac fibrosis, a characteristic of heart failure. To overcome these challenges, this research group developed "cardiac direct reprogramming," a method that directly induces cardiomyocytes from cardiac fibroblasts without using pluripotent stem cells. They have succeeded in achieving cardiac regeneration and improving cardiac fibrosis and function in mouse models of myocardial infarction and heart failure with reduced ejection fraction. Heart failure is divided into two types: heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. Until now, it was unclear whether this method could also be applied to heart failure with preserved ejection fraction, for which there are no effective treatments. Therefore, in this study, the research group developed genetically modified mice in which the expression of cardiac reprogramming genes in cardiac fibroblasts can be freely controlled by drug administration. Using these mice, they demonstrated for the first time in the world that cardiac direct reprogramming can regenerate cardiomyocytes from fibroblasts in heart failure with preserved ejection fraction, leading to improvements in cardiac fibrosis and function. Furthermore, they discovered that the Gata4 gene, one of the cardiac reprogramming genes, is crucial for treating cardiac fibrosis and developed a therapeutic method for heart failure with preserved ejection fraction through the ameliorating effect on cardiac fibrosis by gene transfer of Gata4 alone.
The results of this research were published in Circulation on December 14, 2024 (US Eastern Time).
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