December 13, 2022
University of Tsukuba
Keio University School of Medicine
Cardiomyocytes, the cells that make up the heart, have poor regenerative capacity. For heart failure with severely reduced cardiac function, a heart transplant is the only curative treatment. However, providing sufficient treatment is difficult due to issues such as a shortage of donors. Furthermore, while regenerative medicine using pluripotent stem cells like iPS cells has garnered attention, it also faces challenges, including the potential for tumor formation, low tissue engraftment rates, and limited therapeutic efficacy.
As a potential solution to these challenges, our research group has developed "cardiac direct reprogramming," a method that induces cardiomyocytes directly from cardiac fibroblasts without using stem cells, and has succeeded in regenerating the hearts of mice with acute myocardial infarction. However, it was previously unknown whether this method could be applied to the chronic phase of myocardial infarction, for which there is no effective treatment. In this study, we first developed a new genetically modified mouse model in which the expression of cardiac reprogramming genes can be freely controlled by drug administration, and performed cardiac direct reprogramming. As a result, we demonstrated for the first time in the world that cardiomyocytes can be regenerated from fibroblasts in the chronic phase of myocardial infarction, leading to improved cardiac function. Furthermore, we found that "bad" cardiac fibroblasts, which highly express genes involved in fibrosis (tissue hardening), transform into "good" fibroblasts with low expression of these genes, causing the infarct area (the region where cardiomyocytes have died) to shrink.
This study has revealed that cardiac direct reprogramming improves heart failure in the chronic phase of myocardial infarction through two mechanisms: cardiomyocyte regeneration from cardiac fibroblasts and an anti-fibrotic effect mediated by the conversion of fibroblasts into a "good" phenotype.
For the full press release, please see below.