Blastocyst complementation using Prdm14-deficient rats enables efficient germline transmission and generation of functional mouse spermatids in rats

Toshihiro Kobayashi (), Teppei Goto, Mami Oikawa, Makoto Sanbo, Fumika Yoshida, Reiko Terada, Naoko Niizeki, Naoyo Kajitani, Kanako Kazuki, Yasuhiro Kazuki, Shinichi Hochi, Hiromitsu Nakauchi, M. Azim Surani and Masumi Hirabayashi ()
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Toshihiro Kobayashi: National Institute for Physiological Sciences
Teppei Goto: National Institute for Physiological Sciences
Mami Oikawa: National Institute for Physiological Sciences
Makoto Sanbo: National Institute for Physiological Sciences
Fumika Yoshida: National Institute for Physiological Sciences
Reiko Terada: National Institute for Physiological Sciences
Naoko Niizeki: National Institute for Physiological Sciences
Naoyo Kajitani: Tottori University
Kanako Kazuki: Tottori University
Yasuhiro Kazuki: Tottori University
Shinichi Hochi: Shinshu University
Hiromitsu Nakauchi: The University of Tokyo
M. Azim Surani: University of Cambridge
Masumi Hirabayashi: National Institute for Physiological Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract Murine animal models from genetically modified pluripotent stem cells (PSCs) are essential for functional genomics and biomedical research, which require germline transmission for the establishment of colonies. However, the quality of PSCs, and donor-host cell competition in chimeras often present strong barriers for germline transmission. Here, we report efficient germline transmission of recalcitrant PSCs via blastocyst complementation, a method to compensate for missing tissues or organs in genetically modified animals via blastocyst injection of PSCs. We show that blastocysts from germline-deficient Prdm14 knockout rats provide a niche for the development of gametes originating entirely from the donor PSCs without any detriment to somatic development. We demonstrate the potential of this approach by creating PSC-derived Pax2/Pax8 double mutant anephric rats, and rescuing germline transmission of a PSC carrying a mouse artificial chromosome. Furthermore, we generate mouse PSC-derived functional spermatids in rats, which provides a proof-of-principle for the generation of xenogenic gametes in vivo. We believe this approach will become a useful system for generating PSC-derived germ cells in the future.

Date: 2021
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DOI: 10.1038/s41467-021-21557-x

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