Inhibition of Apoptosis Overcomes Stage-Related Compatibility Barriers to Chimera Formation in Mouse Embryos.
Cell types more advanced in development than embryonic stem cells, such as EpiSCs, fail to contribute to chimeras when injected into pre-implantation-stage blastocysts, apparently because the injected cells undergo apoptosis. Here we show that transient promotion of cell survival through expression of the anti-apoptotic gene BCL2 enables EpiSCs and Sox17+endoderm progenitors to integrate into blastocysts and contribute to chimeric embryos. Upon injection into blastocyst, BCL2-expressing EpiSCs contributed to all bodily tissues in chimeric animals while Sox17+endoderm progenitors specifically contributed in a region-specific fashion to endodermal tissues. In addition, BCL2 expression enabled rat EpiSCs to contribute to mouse embryonic chimeras, thereby forming interspecies chimeras that could survive to adulthood. Our system therefore provides a method to overcome cellular compatibility issues that typically restrict chimera formation. Application of this type of approach could broaden the use of embryonic chimeras, including region-specific chimeras, for basic developmental biology research and regenerative medicine.
Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Hideki
H
Masaki
Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Megumi
M
Kato-Itoh
Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Yusuke
Y
Takahashi
Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Ayumi
A
Umino
Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Hideyuki
H
Sato
Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Keiichi
K
Ito
Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Ayaka
A
Yanagida
Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Toshinobu
T
Nishimura
Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Tomoyuki
T
Yamaguchi
Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki-shi, Aichi-ken 444-0864, Japan.
Masumi
M
Hirabayashi
Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Chuo-ku, Kumamoto 860-8555, Japan.
Takumi
T
Era
Institute for Stem Cell Biology and Regenerative Medicine and Ludwig Center for Cancer Stem Cell Biology and Medicine, Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Kyle M
KM
Loh
Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, Institute for Stem Cell Biology and Regenerative Medicine and Child Health Research Institute, Stanford University School of Medicine, CA 94305, USA.
Sean M
SM
Wu
Institute for Stem Cell Biology and Regenerative Medicine and Ludwig Center for Cancer Stem Cell Biology and Medicine, Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Irving L
IL
Weissman
Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: nakauchi@stanford.edu.
Hiromitsu
H
Nakauchi
D000818:Animals; D017209:Apoptosis; D002678:Chimera / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology*; D053595:Embryonic Stem Cells / Q000166:cytology; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D055747:SOX Transcription Factors / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D055747:SOX Transcription Factors