By introducing just four transcription factor genes into dermal fibroblasts, Dr. Yamanaka succeeded in producing induced pluripotent stem (iPS) cells, which exhibit a pluripotency similar to that of embryonic stem (ES) cells. The iPS cell technology is now expected not only to expand the possibilities of regenerative medicine, but also to make significant contributions to the rapid progress of medical science in general.
The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cell (Mitsui, K., Tokuzawa, Y., Itoh, H., Segawa, K., Murakami, M., Takahashi, K., Maruyama, M., Maeda, M. and Yamanaka, S.). Cell 113: 631-642, 2003.
Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors (Takahashi, K. and Yamanaka, S.). Cell 126: 663-676, 2006.
Generation of germline-competent induced pluripotent stem cells (Okita, K., Ichisaka, T. and Yamanaka, S.). Nature 448: 313-317, 2007.
Induction of pluripotent stem cells from adult human fibroblasts by defined factors (Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K. and Yamanaka, S.). Cell 131: 861-872, 2007.
Suppression of induced pluripotent stem cell generation by the p53-p21 pathway (Hong, H., Takahashi, K., Ichisaka, T., Aoi, T., Kanagawa, O., Nakagawa, M., Okita, K. and Yamanaka, S.). Nature 460: 1132-1135, 2009.
By introducing just four transcription factor genes into dermal fibroblasts, Dr. Shinya Yamanaka succeeded in creating induced pluripotent stem (iPS) cells, which exhibit a pluripotency similar to that of embryonic stem (ES) cells. The iPS cell technology is now expected not only to expand the possibilities of regenerative medicine, but also to make significant contributions to the rapid progress of medical science in general.
ES cells are also expected to offer high potential in regenerative medicine, but they are neither without ethical concerns about the destruction of human embryos, nor free from a risk of immunological rejection.
If a differentiated cell nucleus is transplanted into an enucleated ovum, the expression profile of the genome is reprogrammed into a non-differentiated state. This vital phenomenon has long been recognized, but no one could have foreseen that such a limited number of factors were responsible for this complicated process.
Dr. Yamanaka approached his research from the hypothesis that factors maintaining the pluripotency of ES cells may be able to reprogram a differentiated cell back into a pluripotent state. Utilizing an open database, he identified dozens of genes expressed specifically in ES cells. After carrying out numerous experiments on such genes, he finally succeeded in generating iPS cells with the capacity for self-renewal and pluripotency similar to that of ES cells by introducing four genes (Oct3/4, Sox2, Klf4, c-Myc) into dermal fibroblast cells of mice. Dr. Yamanaka’s research group then went on to generate iPS cells from human fibroblasts using a similar technique.
Dr. Yamanaka’s series of research is extremely original and innovative in that he made it possible to turn back the clock to induce self-renewing pluripotent stem cells from differentiated somatic cells by introducing a small number of transcription factor genes. The iPS cell technology is expected to enable elucidation of the pathologies of intractable diseases and their cures, as well as screening for drug discovery and toxicity tests, thereby making immense contributions to the advancement of not only regenerative medicine, but to the field of medical science as a whole.
For these reasons, the Inamori Foundation is pleased to present the 2010 Kyoto Prize in Advanced Technology to Dr. Shinya Yamanaka.
Research on generating tissues and organs lost as a result of illness or injury has been conducted for several decades. Human embryonic stem (ES) cells, as first reported 12 years ago, have a pluripotent differentiation ability and a high capacity for proliferation, and they are capable of generating cells for any tissues and organs. There have been high expectations that this regenerative medicine will play a significant role in curing numerous intractable diseases. However, there have been underlying issues, such as ethical issues, concerning the sacrifice of fertilized eggs to generate ES cells as well as challenges relating to adverse rejections when the cells are transplanted into a human body.
In order to avoid these issues, we embarked on research to generate embryonic-like stem cells from differentiated cells. After several years of research, with the introduction of merely four genes – Oct3/4, Sox2, Klf4, and c-Myc, we successfully derived induced pluripotent stem (iPS) cells from the skin fibroblasts of a mouse, which was reported in the journal Cell in 2006 for the first time in the world. We also reported the generation of iPS cells from human skin fibroblasts in 2007. Because the established iPS cells from patients have similar characteristics to those of ES cells, iPS cell technology has an enormous potential. It is expected that iPS cells will assist in unraveling the mechanisms for numerous diseases that have challenged researchers, in searching for new drugs, as well as in evaluating both drug effectiveness and adverse effects. Moreover, iPS cells may become a promising source of cell transplant treatments for such diseases as myocardial infarction, diabetes, spinal cord injury, and Parkinson’s disease once the clinical safety of the cells are confirmed and other problems are solved.
Studies confirm that iPS cells have been successfully established from Japanese people of varying ages, and no significant differences have been found among them in terms of pluripotency.
However, from the viewpoint of cell transplantation treatment, challenges still remain concerning time saving for cell generation and cost reduction, not to mention establishing protocols to generate clinical-grade iPS cells. We plan to produce iPS cells from donors having various transplantation matching adaptabilities, and to set up an “iPS cell bank for regeneration medicine.”
Today, researchers at many universities and corporations around the world are participating in iPS cell research, and cell generation methods are rapidly improving. It has been reported that iPS cells have been used to differentiate cells for tissues and organs such as nerves, cardiac muscle, and blood. In the new research building recently completed at Kyoto University, thanks to the extended support of many people, we would like to dedicate our full strength and effort for the next 10 years to develop a new medical science based on iPS cells.