M.D., Ph.D. Professor Mitinori Saitou
The human body consists of a variety of cell types with distinct characters. An essential information code that defines a cell’s unique character is the epigenome, which refers to the whole-genome assembly of epigenetic modifications of chromatin. We are studying the mechanism of germ cell development, which, among all the cell types in the body, shows one of the most dynamic regulations of the epigenome to acquire totipotency, thereby aiming to understand the regulatory basis for many distinct cellular characters and to control them appropriately in vitro.
Research and Education
The germ-cell lineage ensures the creation of new individuals, perpetuating/diversifying the genetic and epigenetic information across the generations. We have been investigating the mechanism for germ-cell development, and have shown that mouse embryonic stem cells (mESCs)/induced pluripotent stem cells (miPSCs) are induced into primordial germ cell-like cells (mPGCLCs) with a robust capacity for both spermatogenesis and oogenesis and for contributing to offspring. These works have served as a basis for elucidating key mechanisms during germ-cell development such as epigenetic reprogramming, sex determination, meiotic entry, and nucleome programming.
By investigating the development of cynomolgus monkeys as a primate model, we have defined a developmental coordinate of pluripotency among mice, monkeys, and humans, identified the origin of the primate germ-cell lineage in the amnion, and have elucidated the X-chromosome dosage compensation program in primates. Accordingly, we have succeeded in inducing human iPSCs (hiPSCs) into human PGCLCs (hPGCLCs) and elucidated the mechanism of human germ-cell specification, demonstrating that the mechanisms for germ-cell specification are evolutionarily divergent in many aspects between humans and mice. Furthermore, we have demonstrated an ex vivo reconstitution of fetal oocyte development in humans and monkeys, and an in vitro induction of meiotic fetal oocytes from ESCs in monkeys. More recently, we have established a robust strategy for inducing epigenetic reprogramming and differentiation of hPGCLCs into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (~>1010-fold). These studies have established a foundation for human in vitro gametogenesis. We are aiming to advance it further to delineate the mechanism of human germ-cell development and to create a basis for new possibilities in reproductive medicine.
Mitotic pro-spermatogonia (top row) and oogonia (bottom row) differentiated from hPGCLCs induced from hiPSCs. Relief contrast images (left column) and fluorescence images for TFAP2C-EGFP (middle column), DAZL-tdTomato (right column, top) or DDX4-tdTomato (right column, bottom) are shown.
Recent Publications
- Murase, Y., Yokogawa, R., Yabuta, Y., Nagano, M., Katou, Y., Mizuyama, M., Kitamura, A., Puangsricharoen, P., Yamashiro, C., Hu, B., Mizuta, K., Ogata, K., Ishihama, Y., and Saitou, M. (2024). In vitro reconstitution of epigenetic reprogramming in the human germ line, Nature, 631, 170-178.
- Gyobu-Motani, S., Yabuta, Y., Ken Mizuta, K., Katou, Y., Okamoto, I., Kawasaki, M., Kitamura, A., Tsukiyama, T., Iwatani, C., Tsuchiya, H., Tsujimura, T., Yamamoto, T., Nakamura, T., and Saitou, M. (2023). Induction of fetal meiotic oocytes from embryonic stem cells in cynomolgus monkeys, The EMBO Journal, 42: e112962.
- Mizuta, K., Katou, Y., Nakakita, B., Kishine, A., Nosaka, Y., Saito, S., Iwatani, C., Tsuchiya, H., Kawamoto, I., Nakaya, M., Tsukiyama, T., Nagano, M., Kojima, Y., Nakamura, T., Yabuta, Y., Horie, A., Mandai, M., Ohta, H., and Saitou, M. (2022). Ex vivo reconstitution of fetal oocyte development in humans and monkeys, The EMBO Journal, 41: e110815.
- Nagano, M., Hu, B., Yokobayashi, S., Yamamura, A., Umemura, F., Coradin, M., Ohta, H., Yabuta, Y., Ishikura, Y., Okamoto, I., Ikeda, H., Kawahira, N., Nosaka, Y., Shimizu, S., Kojima, Y., Mizuta, K., Kasahara, T., Imoto, Y., Meehan, K., Stocsits, R., Wutz, G., Hiraoka, Y., Murakawa, Y., Yamamoto, T., Tachibana, K., Peters, J.M., Mirny, L.A., Garcia, B.A., Majewski, J., and Saitou, M. (2022). Nucleome programming is required for the foundation of totipotency in mammalian germline development, The EMBO Journal, 41: e110600.
- Okamoto, I., Nakamura, T., Sasaki, K., Yabuta, Y., Iwatani, C., Tsuchiya, H., Nakamura, S., Ema, M., Yamamoto, T., and Saitou, M. (2021). The X-chromosome dosage compensation program during the development of cynomolgus monkeys, Science, 374, eabd8887.
Laboratory
Professor: Mitinori Saitou
Associate Professor: Hiroshi Ohta
Program Specific Associate Professor: Tomonori Nakamura
Program-Specific Senior Lecturer: Ikuhiro Okamoto
Program-Specific Senior Lecturer (CiRA): Shihori Yokobayashi
Assistant Professor: Masahiro Nagano
Assistant Professor: Ken Mizuta
Program Specific Assistant Professor: Yukihiro Yabuta
Tel: +81-75-753-4335
Fax: +81-75-751-7286
e-mail: saitou@anat2.med.kyoto-u.ac.jp