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Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells

Cell. 2010 Sep 3;142(5):787-99
Toshihiro Kobayashi,1,2 Tomoyuki Yamaguchi,1,2 Sanae Hamanaka,1,2 Megumi Kato-Itoh,2,3 Yuji Yamazaki,1,2 Makoto Ibata,2 Hideyuki Sato,1,2 Youn-Su Lee,1,2 Jo-ichi Usui,1,6 A.S. Knisely,5 Masumi Hirabayashi,3,4 and Hiromitsu Nakauchi1,2,*
1 Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan 2 Japan Science Technology Agency, ERATO, Nakauchi Stem Cell and Organ Regeneration Project, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan 3 Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan 4 School of Life Science, The Graduate University for Advanced Studies, Okazaki, Aichi 444-8585, Japan 5 Institute of Liver Studies, King’s College Hospital, London SE5 9RS, UK 6 Present address: Department of Nephrology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan

The complexity of organogenesis hinders in vitro generation of organs derived from a patient's pluripotent stem cells (PSCs), an ultimate goal of regenerative medicine. Mouse wild-type PSCs injected into Pdx1(-/-) (pancreatogenesis-disabled) mouse blastocysts developmentally compensated vacancy of the pancreatic "developmental niche," generating almost entirely PSC-derived pancreas. To examine the potential for xenogenic approaches in blastocyst complementation, we injected mouse or rat PSCs into rat or mouse blastocysts, respectively, generating interspecific chimeras and thus confirming that PSCs can contribute to xenogenic development between mouse and rat. The development of these mouse/rat chimeras was primarily influenced by host blastocyst and/or foster mother, evident by body size and species-specific organogenesis. We further injected rat wild-type PSCs into Pdx1(-/-) mouse blastocysts, generating normally functioning rat pancreas in Pdx1(-/-) mice. These data constitute proof of principle for interspecific blastocyst complementation and for generation in vivo of organs derived from donor PSCs using a xenogenic environment.