Generation of lung organs from mouse embryonic stem cells via blastocyst complementation in mice

• Project/Area Number: 18K15921
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Niigata University
• Principal Investigator: Zhou Qiliang 新潟大学, 医歯学系, 助教 (10770232)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肺再生 / 胚盤胞補完法 / 多能性幹細胞 / ES細胞

Outline of Final Research Achievements

We succeeded in the generation of lungs using mouse embryonic stem cells (ESCs) in apneumic Fgf10 Ex1mut/Ex3mut mice by blastocyst complementation. Complementation
with ESCs enables Fgf10-deficient mice to survive to adulthood without abnormalities. Both the generated lung alveolar parenchyma and the interstitial portions, including vascular endothelial cells, vascular and parabronchial smooth muscle cells, and connective tissue, largely originate from the injected ESCs.
Our data suggest that Fgf10 Ex1mut/Ex3mut blastocysts provide an organ niche for lung generation and that blastocyst complementation could be a viable approach for generating whole lungs.

Academic Significance and Societal Importance of the Research Achievements

多くの重症肺疾患においては肺移植しか救命の道がない。しかし、絶対的なドナー不足と移植後の免疫拒絶が深刻な問題となる。多能性幹細胞を用いる肺臓器作成ができれば、上記問題の克服が可能となる。しかし肺は複雑な3次元構造を持ち、かつ多数の細胞種からなる複雑な臓器であり、in vitro での移植に耐えうる肺臓器の再構築は極めて難しいと考えられる。本研究の胚盤胞補完法を用いるin vivoでの肺再生技術を発展させ、異種間キメラや大型動物における肺臓器創出技術の確立への展開することにより、肺移植を目指すための肺臓器再生研究または肺疾患解明や新薬開発のためのモデル動物開発に大きく貢献するものと期待される。

Research Products

• [Journal Article] Generation of Lungs by Blastocyst Complementation in Apneumic Fgf10-Deficient Mice (2020)
  • Author(s): Kitahara Akihiko、Ran Qingsong、Oda Kanako、Yasue Akihiro、Abe Manabu、Ye Xulu、Sasaoka Toshikuni、Tsuchida Masanori、Sakimura Kenji、Ajioka Yoichi、Saijo Yasuo、Zhou Qiliang
  • Journal Title: Cell Reports Volume: 31 Issue: 6 Pages: 107626-107626
  • DOI: 10.1016/j.celrep.2020.107626
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNAs control eyelid development through regulating Wnt signaling. (2019)
  • Author(s): Nagai T, Trakanant S, Kawasaki M, Kawasaki K, Yamada Y, Watanabe M, Blackburn J, Otsuka-Tanaka Y, Hishinuma M, Kitatmura A, Meguro F, Yamada A, Kodama Y, Maeda T, Zhou Q, Saijo Y, Yasue A, Sharpe PT, Hindges R, Takagi R, Ohazama A.
  • Journal Title: Dev Dyn Volume: 248 Issue: 3 Pages: 201-210
  • DOI: 10.1002/dvdy.10
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 胚盤胞補完法とES細胞を用いたマウス生体内における肺臓器再生 (2019)
  • Author(s): 冉慶松，周啓亮，北原 哲彦，叶許緑，佐々木 健太，齋木 琢郎，松本吉史，森山雅人，泰江 章博，笹岡 俊邦，小田加奈子，阿部 学，味岡洋一 ，西條康夫
  • Organizer: 第18回日本再生医療学会総会
• [Presentation] GENERATION OF LUNG ORGANS FROM MOUSE EMBRYONIC STEM CELLS VIA BLASTOCYST COMPLEMENTATION IN MICE (2019)
  • Author(s): Q Zhou, Q Ran, A Kitahara, X Ye, K Sasaki, Y Matsumoto, M Moriyama, K Oda, T Sasaoka, M Abe, K Sakimura, Y Ajioka, A Yasue, and Y Saijo
  • Organizer: International Society for Stem Cell Research
  • Int'l Joint Research
• [Presentation] 胚盤胞補完法とES細胞を用いたマウス生体内における肺臓器再生 (2019)
  • Author(s): 冉慶松，周啓亮，北原 哲彦，叶許緑，佐々木 健太，齋木 琢郎 ，松本吉史，森山雅人，泰江 章博，笹岡 俊邦，小田加奈子，阿部 学，味岡洋一，西條康夫
  • Organizer: 第18回日本再生医療学会総会
• [Presentation] Generation of Lung Organs From Embryonic Stem Cells via Blastocyst Complementation in Mice (2018)
  • Author(s): Akihiko Kitahara, Yuki Shimizu, Tatsuya Goto, Seijiro Sato, Terumoto Koike, Masanori Tsuchida
  • Organizer: 第70回日本胸部外科学会定期学術集会
• [Remarks] マウス生体内でES細胞由来肺臓器を創出しました－肺疾患解明や肺再生研究へ新しい道－
  • URL: https://www.niigata-u.ac.jp/news/2020/72503/