As most people know, procreation depends on the fusion of two germ cells, sperm and oocytes, which transfers genetic and epigenetic information of the parents to the offspring. We are investigating the genetic and epigenetic mechanisms that determine the development of germ cells. These studies will also examine how aberrations in these mechanisms lead to related diseases such as infertility and genetic abnormalities in offspring.
We have successfully generated primordial germ cell-like cells (PGCLC) in vitro from mouse ESCs and iPSCs. As the name suggests, these cells behave like primordial germ cells, which are responsible for producing sperm and oocytes. We confirmed that these cells contribute to the generation of healthy offspring. We have used our PGCLC as a model to investigate a number of determinants in germ cell development including the transcription and signaling factors responsible for their induction from PS cells and the epigenome reprogramming mechanism. We have also established methods for the proliferation of PGCLCs and their differentiation to spermatogonial stem cells in vitro. Finally, using mouse PGCLCs as our model, we are investigating oocyte development, meiosis, and the effects of sex chromosome abnormalities on fertility.
We have also generated PGCLCs from human iPSCs, having compared the induction efficiencies for germ lineage between iPSC clones and found the molecular and signaling factors responsible for the different efficiencies. Experiments with cynomolgus monkey iPSC-derived PGCLCs have allowed us to analyze germ lineage development across different mammalian species and identify the early amniotic membrane as the origin of germ cells in primates.
We aim to extend these primate projects to the study of human germ cell development.
Yamashiro, C., Sasaki, K., Yabuta, Y., Kojima, Y., Nakamura, T., Okamoto, I., Yokobayashi, S., Murase, Y., Ishikura, Y., Shirane, K., Sasaki, H., Yamamoto, T., and Saitou, M. (2018). Generation of human oogonia from induced pluripotent stem cells in vitro, Science, 362, 356-360.
Kojima, Y., Sasaki, K., Yokobayashi, S., Sakai, Y., Nakamura, T., Yabuta, Y., Nakaki, F., Nagaoka, S., Woltjen, K., Hotta, A., Yamamoto, T., and Saitou, M. (2017). Evolutionarily Distinctive Transcriptional and Signaling Programs Drive Human Germ Cell Lineage Specification from Pluripotent Stem Cells, Cell Stem Cell, 21, 517-532.
Miyauchi, H., Ohta, H., Nagaoka, S., Nakaki, F., Sasaki, K., Hayashi, K., Yabuta, Y., Nakamura, T., Yamamoto, T., and Saitou, M. (2017). Bone morphogenetic protein and retinoic acid synergistically specify female germ cell fate in mice, The EMBO Journal, 36, 3100-3119.
Hirota, T., Ohta, H., Powell, B. E., Mahadevaiah, S., K., Ojarikre, O. A., *Saitou, M., and *Turner, J. M. A. (2017). Fertile offspring from sterile sex chromosome trisomic mice, Science, 357, 932-935. * Co-correspondence
Ishikura, Y., Yabuta, Y., Ohta, H., Hayashi, K., Nakamura, T., Okamoto, I., Yamamoto, T., Kurimoto, K., Shirane, K., Sasaki, H., and Saitou, M. (2016). In Vitro Derivation and Propagation of Spermatogonial Stem Cell Activity from Mouse Pluripotent Stem Cells, Cell Reports, 17, 2789-2804.
Sasaki, K., Nakamura, T., Okamoto, I., Yabuta, Y., Iwatani, C., Tsuchiya, H., Seita, Y., Nakamura, S., Shiraki, N., Takakuwa, T., Yamamoto, T., and Saitou, M. (2016). The Germ Cell Fate of Cynomolgus Monkeys is Specified in the Nascent Amnion, Developmental Cell, 39, 169-185.
Nakamura, T., Okamoto, I., Sasaki, K., Yabuta, Y., Iwatani, C., Tsuchiya, H., Seita, Y., Nakamura, S., Yamamoto, T., and Saitou, M. (2016). A developmental coordinate of pluripotency among mice, monkeys, and humans, Nature, 537, 57-62.
Saitou, M. and Miyauchi, H. (2016). Gametogenesis from Pluripotent Stem Cells, Cell Stem Cell, 18, 721-735.
Sasaki, K., Yokobayashi, S., Nakamura, T., Okamoto, I., Yabuta, Y., Kurimoto, K., Ohta, H., Moritoki, Y., Iwatani, C., Tsuchiya, H., Nakamura, S., Sekiguchi, K., Sakuma, T., Yamamoto, T., Mori, T., Woltjen, K., Nakagawa, M., Yamamoto, T., Takahashi, K., Yamanaka, S., and Saitou, M. (2015). Robust In Vitro Induction of Human Germ Cell Fate from Pluripotent Stem Cells, Cell Stem Cell, 17, 178-194.
Kurimoto, K., Yabuta, Y., Hayashi, K., Ohta, H., Kiyonari, H., Mitani, T., Moritoki, Y., Kohri, K., Kimura, H., Yamamoto, T., Katou, Y., Shirahige, K., and Saitou, M. (2015). Quantitative Dynamics of Chromatin Remodeling during Germ Cell Specification from Mouse Embryonic Stem Cells, Cell Stem Cell, 16, 517-532