An interspecies barrier to tetraploid complementation and chimera formation

• Project/Area Number: 17K08623
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: Yamaguchi Tomoyuki 東京大学, 医科学研究所, 特任准教授 (80392158)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 異種間キメラ / 多能性幹細胞 / 発生 / 細胞間相互作用 / 異種キメラ / キメリズム / 異種間テトラプロイドコンプリメンテーション

Outline of Final Research Achievements

To study development of the conceptus in xenogeneic environments, we assessed interspecies chimera formation as well as tetraploid complementation between mouse and rat. Overall contribution of donor PSC-derived cells was lower in interspecies chimeras than in intraspecies chimeras, and high donor chimerism was associated with anomalies or embryonic death. Organ to organ variation in donor chimerism was greater in interspecies chimeras than in intraspecies chimeras, suggesting species-specific affinity differences among interacting molecules necessary for organogenesis.
In interspecies tetraploid complementation, embryo development was near normal until the stage of placental formation, after which no embryos survived.

Academic Significance and Societal Importance of the Research Achievements

異種間キメラの作製は動物体内での臓器作製法である胚盤胞補完法の基礎となる技術であり、多能性幹細胞が動物の発生過程に協調できるかどうかは臓器作製の可否に非常に重要な情報である。本研究で、多能性幹細胞は異種の発生環境に完全に協調できる訳ではなく、組織によって器官形成に重要な細胞間相互作用ができないという結果が得られた。多能性幹細胞が寄与できない異種組織では、細胞間相互作用に必要な分子の種を合わせるといった遺伝子改変が動物体内に多能性幹細胞由来の臓器を作製する上で必要となると考えられる。

Research Products

• [Journal Article] Long-term eradication of extranodal natural killer/T-cell lymphoma, nasal type, by induced pluripotent stem cell-derived Epstein-Barr virus-specific rejuvenated T cells in vivo (2020)
  • Author(s): Ando M, Ando J, Yamazaki S, Ishii M, Sakiyama Y, Harada S, Honda T, Yamaguchi T, Nojima M, Ohshima K, Nakauchi H, Komatsu N
  • Journal Title: Haematologica Volume: 105 Issue: 3 Pages: 796-807
  • DOI: 10.3324/haematol.2019.223511
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Compensation of Disabled Organogeneses in Genetically Modified Pig Fetuses by Blastocyst Complementation. (2020)
  • Author(s): Matsunari H, Watanabe M, Hasegawa K, Uchikura A, Nakano K, Umeyama K, Masaki H, Hamanaka H, Yamaguchi T, Nagaya M, Nishinakamura R, Nakauchi H, Nagashima H.
  • Journal Title: Stem Cell Reports. Volume: 14(1) Issue: 1 Pages: 21-33
  • DOI: 10.1016/j.stemcr.2019.11.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] iPSC-Derived Organs In Vivo: Challenges and Promise. (2018)
  • Author(s): Suchy F, Yamaguchi T, Nakauchi H.
  • Journal Title: Cell Stem Cell. Volume: 22(1) Issue: 1 Pages: 21-24
  • DOI: 10.1016/j.stem.2017.12.003
  • Peer Reviewed
• [Journal Article] In vitro platform of allogeneic stem cell-derived cardiomyocyte transplantation for cardiac conduction defects. (2018)
  • Author(s): Yoshida A, Lee JK, Tomoyama S, Miwa K, Shirakawa K, Hamanaka S, Yamaguchi T, Nakauchi H, Miyagawa S, Sawa Y, Komuro I, Sakata Y.
  • Journal Title: Europace. Volume: 20(9) Issue: 9 Pages: 1553-1560
  • DOI: 10.1093/europace/eux379
  • Peer Reviewed
• [Journal Article] Chimeric liver transplantation reveals interspecific graft remodelling. (2018)
  • Author(s): Oldani G, Peloso A, Vijgen S, Wilson EM, Slits F, Gex Q, Morel P, Delaune V, Orci LA, Yamaguchi T, Kobayashi T, Rubbia-Brandt L, Nakauchi H, Lacotte S, Toso C.
  • Journal Title: J Hepatol. Volume: 69(5) Issue: 5 Pages: 1025-1036
  • DOI: 10.1016/j.jhep.2018.07.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation of Vascular Endothelial Cells and Hematopoietic Cells by Blastocyst Complementation. (2018)
  • Author(s): Hamanaka S, Umino A, Sato H, Hayama T, Yanagida A, Mizuno N, Kobayashi T, Kasai M, Suchy FP, Yamazaki S, Masaki H, Yamaguchi T, Nakauchi H.
  • Journal Title: Stem Cell Reports. Volume: 11(4) Issue: 4 Pages: 988-997
  • DOI: 10.1016/j.stemcr.2018.08.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An interspecies barrier to tetraploid complementation and chimera formation. (2018)
  • Author(s): Yamaguchi T, Sato H, Kobayashi T, Kato-Itoh M, Goto T, Hara H, Mizuno N, Yanagida A, Umino A, Hamanaka S, Suchy F, Masaki H, Ota Y, Hirabayashi M, Nakauchi H.
  • Journal Title: Sci Rep. Volume: 8(1) Pages: 15289-15289
  • Peer Reviewed
• [Journal Article] Intra-embryo Gene Cassette Knockin by CRISPR/Cas9-Mediated Genome Editing with Adeno-Associated Viral Vector. (2018)
  • Author(s): Mizuno N, Mizutani E, Sato H, Kasai M, Ogawa A, Suchy F, Yamaguchi T, Nakauchi H.
  • Journal Title: iScience. Volume: 9 Pages: 286-297
  • DOI: 10.1016/j.isci.2018.10.030
  • Peer Reviewed
• [Presentation] 異種動物体内での臓器創出と移植 (2020)
  • Author(s): 山口智之
  • Organizer: 第22回日本異種移植研究会
  • Invited
• [Presentation] 動物の発生環境を利用した臓器作製 (2019)
  • Author(s): 山口智之
  • Organizer: 第46回日本臓器保存生物医学会学術集会
  • Invited
• [Presentation] 動物の発生環境を利用した臓器作製 (2019)
  • Author(s): 山口智之
  • Organizer: 第51回日本臨床分子形態学会総会
  • Invited
• [Presentation] 異種キメラから得られた知見 (2019)
  • Author(s): 山口智之
  • Organizer: 第2回再生学異分野融合研究会
  • Invited
• [Presentation] AAVベクターを利用したCRISPR/Cas9システムによる受精卵遺伝子ノックイン (2019)
  • Author(s): 山口智之
  • Organizer: 第4回日本ゲノム編集学会
  • Invited
• [Presentation] 動物体内に作成した膵臓と移植治療の可能性 (2018)
  • Author(s): 山口智之
  • Organizer: 第35回東北インスリン研究会
  • Invited
• [Presentation] 異種動物体内での臓器作製 (2018)
  • Author(s): 山口智之
  • Organizer: 第1回再生学異分野融合研究会
  • Invited
• [Presentation] Interspecies organogenesis generates autologous functional islets (2018)
  • Author(s): 山口智之
  • Organizer: 第24回日本遺伝子細胞治療学会
  • Invited
• [Presentation] 胚盤胞補完法を用いた実質臓器再生 (2018)
  • Author(s): 山口智之
  • Organizer: 第63回日本透析医学会
  • Invited
• [Presentation] 動物の体内にヒトの膵臓をつくる！ (2018)
  • Author(s): 山口智之
  • Organizer: 日本IDDMネットワークシンポジウム
  • Invited
• [Presentation] Generation of “whole organ” by interspecies organogenesis (2018)
  • Author(s): 山口智之
  • Organizer: 第70回日本細胞生物学会
  • Invited
• [Presentation] 異種動物体内での膵臓再生と糖尿病治療 (2018)
  • Author(s): 山口智之
  • Organizer: 第3回 生活習慣病とがんの代謝栄養メカニズム研究会
  • Invited
• [Presentation] 異種動物体内での膵臓作製と糖尿病治療 (2018)
  • Author(s): 山口智之
  • Organizer: 明治大学バイオリソース研究国際インスティテュート 公開シンポジウム
  • Invited
• [Presentation] 動物体内での膵臓作製と糖尿病治療 (2018)
  • Author(s): 山口智之
  • Organizer: 御茶ノ水GEM Seminar
  • Invited
• [Presentation] 異種動物体内における膵臓作製と糖尿病治療 (2018)
  • Author(s): 山口智之
  • Organizer: 第11回 ラットリソースリソース研究会
  • Invited
• [Book] 糖尿病学 2018 (2018)
  • Author(s): 山口智之
  • Total Pages: 168
  • Publisher: 診断と治療社
  • ISBN: 9784787823472
• [Book] 消化器疾患の最新医療 (2018)
  • Author(s): 山口智之
  • Total Pages: 485
  • Publisher: 寺田国際事務所/先端医療技術研究所
  • ISBN: 9784925089616