A major bottleneck in regenerative medicine is the limited availability of transplantable organs. Inspired by the fact that successful engraftment of hematopoietic stem cells requires the creation of empty niches through myeloablation, we developed the concept of an “organ niche”. We pioneered intra- and interspecies blastocyst complementation technology, demonstrating functional organ generation from pluripotent stem cells (PSCs) in rodents and large animals. We are currently working on generating human iPSC derived organs in both rodents and large animals. The current bottle neck is the limited contribution of human iPSCs to early embryos. We believe that this inefficiency stems from what we term the xenobarrier—a set of intrinsic barriers that eliminate foreign cells during early embryonic development. Elucidating the mechanism of the xenobarrier and overcoming xenobarrier is our primary focus.
Representative publications:
1. Kobayashi, T., Yamaguchi, T., Hamanaka, S., Kato-Itoh, M., Yamazaki, Y., Ibata, M., ... & Nakauchi, H. (2010). Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell, 142(5), 787-799.
2. Matsunari, H., Nagashima, H., Watanabe, M., Umeyama, K., Nakano, K., Nagaya, M., ... & Nakauchi, H. (2013). Blastocyst complementation generates exogenic pancreas in vivo in apancreatic cloned pigs. Proceedings of the National Academy of Sciences, 110(12), 4557-4562.
3. Masaki, H., Kato-Itoh, M., Takahashi, Y., Umino, A., Sato, H., Ito, K., ... & Nakauchi, H. (2016). Inhibition of apoptosis overcomes stage-related compatibility barriers to chimera formation in mouse embryos. Cell Stem Cell, 19(5), 587-592.
4. Yamaguchi, T., Sato, H., Kato-Itoh, M., Goto, T., Hara, H., Sanbo, M., ... & Nakauchi, H. (2017). Interspecies organogenesis generates autologous functional islets. Nature, 542(7640), 191-196.
5. Yamaguchi, T., Sato, H., Kobayashi, T., Kato-Itoh, M., Goto, T., Hara, H., ... & Nakauchi, H. (2018). An interspecies barrier to tetraploid complementation and chimera formation. Scientific Reports, 8(1), 15289.
6. Matsunari, H., Watanabe, M., Hasegawa, K., Uchikura, A., Nakano, K., Umeyama, K., ... & Nagashima, H. (2020). Compensation of disabled organogeneses in genetically modified pig fetuses by blastocyst complementation. Stem Cell Reports, 14(1), 21-33.
7. Nishimura, T., Suchy, F. P., Bhadury, J., Igarashi, K. J., Charlesworth, C. T., & Nakauchi, H. (2021). Generation of functional organs using a cell-competitive niche in intra-and inter-species rodent chimeras. Cell Stem Cell, 28(1), 141-149. 8. Nagano, H., Mizuno, N., Sato, H., Mizutani, E., Yanagida, A., Kano, M., ... & Nakauchi, H. (2024). Skin graft with dermis and appendages generated in vivo by cell competition. Nature Communications, 15(1), 336
