| - Field of Regeneration Control, Institute for Frontier Medical Sciences |
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Stem Cell Biology
| Embryonic stem (ES) cells are pluripotent stem cells derived from inner cell mass of mammalian blastocysts. Pluripotency and rapid proliferation make human ES cells attractive sources for cell therapy. However, clinical application of ES cells is confronted with ethical objections against utilizing human embryos. The ultimate goal of our laboratory is to generate ES-like cells directly from somatic cells by nuclear reprogramming. To this end, we are trying to understand molecular mechanisms underlying pluripotency and rapid proliferation of ES cells and to identify factors that induce reprogramming. | |
 Shinya Yamanaka, M.D., Ph.D.
Professor | |
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Research and Education
| Our lab members have diverse backgrounds, graduated from schools of medicine, pharmacy, science, technology and agriculture. We are studying molecular fundamentals of mammalian cells, but also pursuing clinical applications of our basic findings. Our ultimate goal is nuclear reprogramming, which convert adult cells back into embryonic state. If we can make pluripotent ES-like cells directly from patients' somatic cells, that will be tremendous advantage in regenerative medicine. To date, reprogramming has been achieved by nuclear transfer to oocytes or fusion with ES cells. These two methods still require embryos and/or embryo-derived cells. In order to avoid using embryos, it is essential to identify factors that induce reprogramming. Searching of "reprogramming factors" is a hot and competitive race among many laboratories. We demonstrated generation of induced pluripotent stem (iPS) cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4. iPS cells are similar to embryonic stem (ES) cells in morphology, proliferation and teratoma formation. We also established iPS cells from adult human dermal fibroblasts by introducing same four factors. Human iPS cells formed tightly packed and flat colonies. Each cell exhibited morphology similar to that of human ES cells, characterized by large nuclei and scant cytoplasm. Reactivation of the c-Myc retrovirus, however, results in an increased tumorigenicity in the chimeras and progeny mice, thus hindering clinical applications. We developed a modified protocol without using the Myc retrovirus. Elimination of c-Myc drastically reduces tumorigenesis, as measured by cancer-related deaths of chimeric mice derived from iPS cells. Furthermore, we were able to generate human iPS cells from adult dermal fibroblasts without MYC. We also generated iPS cells from adult mouse liver and stomach cells. We also succeeded that generation of mouse iPS cells without transgene integration into genome by using plasmid DNA. We would like to establish clinical-grade iPS cells for investigation for etiology of diseases, toxicology, drug screening, and future cell transplantation therapy. |
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Germline chimaeras from Nanog-iPS cells (F1). |
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Human iPS cells derived from adult human dermal fibroblasts. |
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Chimeric mice obtained by blastocyst injection of Myc- iPS cells derived from mouse embryonic fibroblasts (left, green) or tail-tip fibroblasts (right, red). |
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Laboratory members |
| Recent Publications |
| 1. |
Okita, K., Nakagawa, M., Hong, H., Ichisaka, T., Yamanaka, S.
Generation of Mouse Induced Pluripotent Stem Cells Without Viral Vectors.
Science 322: 949-953, 2008. |
| 2. |
Aoi, T., Yae, K., Nakagawa, M., Ichisaka, T., Okita, K., Takahashi, K., Chiba, T., and Yamanaka, S.
Generation of Pluripotent Stem Cells from Adult Mouse Liver and Stomach Cells.
Science 321:699-702, 2008. |
| 3. |
Nakagawa, M., Koyanagi, M., Tanabe, K., Takahashi, K.,Ichisaka, T., Aoi, T., Okita, K., Mochiduki, Y., Takizawa, N.,and Yamanaka, S.
Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts.
Nat Biotechnol. Nat.Biotechnol 26:101-106, 2008. |
| 4. |
Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S.
Induction of pluripotent stem cells from adult human fibroblasts by defined factors.
Cell 131:861-872, 2007. |
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Okita, K., Ichisaka, T., and Yamanaka, S.
Generation of germline-competent induced pluripotent stem cells.
Nature 448:313-317, 2007. | | | | |
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