2018/08/17
University of Tsukuba
Keio University School of Medicine
National Institute of Advanced Industrial Science and Technology (AIST)
Japan Agency for Medical Research and Development (AMED)
A research group led by Professor Masaki Ieda (Cardiovascular Medicine) of the Faculty of Medicine, University of Tsukuba; Assistant Professor Itaro Sadahiro (Cardiovascular Medicine) of the Keio University School of Medicine; and Naoki Goshima, Research Team Leader at the Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), has discovered that cardiac mesoderm cells can be directly induced from fibroblasts and mouse/human pluripotent stem cells simply by introducing a gene called Tbx6.
Previously, the common method for inducing cardiomyocytes from pluripotent stem cells involved using multiple soluble factors to first induce cardiac mesoderm cells, which are cardiac stem cells, and then subsequently induce cardiomyocytes. However, this conventional method had several issues: 1) the induction process was complex, 2) the induction efficiency was unstable, and 3) the soluble factors were expensive. Professor Ieda's group has previously reported on a new cardiac regeneration method, demonstrating that cardiomyocytes can be directly generated in vivo in mice by introducing cardiomyocyte-inducing genes into cardiac fibroblasts (cells in the heart other than cardiomyocytes). However, this method had limitations, such as the inability to generate other cell types like vascular cells and the fact that the generated cardiomyocytes could not proliferate.
In this study, the research group discovered Tbx6, a gene that directly induces cardiac mesoderm cells from fibroblasts. Furthermore, by introducing Tbx6 into pluripotent stem cells such as mouse ES cells and human iPS cells, they successfully generated proliferative cardiac mesoderm cells efficiently without using soluble factors, and subsequently induced these into cardiomyocytes and vascular cells. They clarified the underlying mechanism: Tbx6 transiently increases the expression of the Mesp1 and BMP4 genes, which are crucial for cardiac development, thereby inducing cardiomyocytes. Moreover, by adjusting the duration of Tbx6 expression, they found it was also possible to induce skeletal muscle and cartilage cells, which also differentiate from the mesoderm. This led to the discovery that Tbx6 is a key factor controlling not only cardiac differentiation but the entire mesodermal differentiation from pluripotent stem cells.
This research has led to the development of a new method for generating cardiomyocytes and vascular cells by introducing Tbx6, without the use of soluble factors. These findings are expected to contribute to the development of a simple, rapid, and inexpensive cardiomyocyte generation technology. This will not only be applicable to regenerative medicine for various heart diseases, including myocardial infarction and dilated cardiomyopathy, but will also be beneficial for drug development.
*The results of this research were published in "Cell Stem Cell" on August 9, 2018 (12:00 AM, August 10, Japan Standard Time).
For the full press release, please see below.