Stem Cell Biology, Developmental Engineering
|Yamanaka, Shinya||Professor / Director of the Center for
iPS Cell Research and Application (CiRA)
|Hotta, Akitsu||Assistant Professor|
|Watanabe, Akira||Assistant Professor|
|Fujimoto, Naoko||Research Associate|
|Nakamura, Masahiro||Research Associate|
|Semi, Katsunori||Research Associate|
|Sone, Masamitsu||Research Associate|
|Miki, Kenji||Research Associate|
|Sato, Takahiro||Research Associate|
Our research group is focused on stem cell biology and developmental engineering. In particular, we have established mouse and human induced pluripotent stem cells (iPS cells), and we are carrying out various aspects of basic and applied research using iPS cell technology.
iPS cells can be generated from a wide range of somatic cell types, and many different methods have been developed for their generation.However, it remains controversial whether iPS cells are distinguishable from ES cells. Using cell biology methods, including in vitro differentiation induction, and molecular biology methods, we plan to evaluate the pluripotency and safety of these cell types. By expanding our understanding of the mechanisms that underlie reprogramming and pluripotency, we aim to generate and culture iPS cells compatible for use in clinical applications. We also seek to use patient-specific iPS cells to study disease mechanisms and applications in drug development.
Using the viral vector transgene delivery system which drives the undifferentiated pluripotent stem cell-specific expression of GFP and drug-resistance genes as a high-efficiency method of selecting human iPS cells, we have facilitated the derivation of various patient-specific iPS cell lines and investigated the intra-nuclear changes that accompany the reprogramming process. With this platform, we will develop techniques for the generation and selection of safer human iPS cells, aiming for a novel iPS cell-based gene therapy approach to the treatment of hemophilia and other genetic disorders.
Using a drug-regulated transgenic mouse system, we are examining the role of iPS cell reprogramming factors in various somatic cells. Prematurely terminated reprogramming reverts cells back towards their original state, suggesting retention of an epigenetic memory. We are examining the chromatin changes induced by transcription factors leading to repression of key differentiation genes and stabilization of pluripotency. Understanding this mechanism may help to enhance reprogramming efficiencies and generate higher quality iPS cells. Also we have developed transposons as non-viral transgene delivery vectors for iPS cell reprogramming. Now, we are applying modifications of transposon technology to address genetic modification, gene discovery (functional annotation) and disease modeling in human iPS cells.
In order to apply iPS cells in a clinical setting, the risk of tumorigenesis from iPS cell-derived cells is to be eliminated. We are now trying to understand the mechanisms how tumor cells arise from iPS cell-derived cells to develop the safer methods of clinical application of iPS cells. We also expand the iPS cell research to understand the cancer biology, by applying the technology for inducing iPS cells to cancer cells in order to change the epigenetic status of cancer cells. Such epigenetically modified cancer cells may be useful to uncover the role of epigenetic control in cancer development.
- Okita K, Yamakawa T, Matsumura Y, Sato Y, Amano N, Watanabe A, Goshima N, Yamanaka S. Stem Cells. 3, 458-66 (2013).
- Maekawa, M., Yamaguchi, K., Nakamura, T., Shibukawa, R., Kodanaka, I., Ichisaka, T., Kawamura, Y., Mochizuki, H., Goshima, N. and Yamanaka, S. Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1. Nature 474, 225-229 (2011).
- Yamada, Y., Aoki, H., Kunisada, T. and Hara, A. Rest promotes the early differentiation of mouse ESCs but is not required for their maintenance. Cell stem cell 6, 10-15 (2010).
- Hotta, A., Cheung, A.Y., Farra, N., Vijayaragavan, K., Seguin, C.A., Draper, J.S., Pasceri, P., Maksakova, I.A., Mager, D.L., Rossant, J., Bhatia, M. and Ellis, J. Isolation of human iPS cells using EOS lentiviral vectors to select for pluripotency. Nat. Methods 6, 370-376 (2009).
- Yoshida, Y., Takahashi, K., Okita, K., Ichisaka, T. and Yamanaka, S. Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell 5, 237-241 (2009).
Center for iPS Cell Research and Application (CiRA)