Platelets have an essential role in lung development via CLEC-2/podoplanin signaling

• Project/Area Number: 16K19572
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: University of Yamanashi
• Principal Investigator: TSUKIJI Nagaharu 山梨大学, 大学院総合研究部, 助教 (20710362)
• Research Collaborator: INOUE Katsue (SUZUKI Katsue) ; OZAKI Yukio ; MORIMOTO Mitsuru ; SASAKI Tomoyuki ; SHIRAI Toshiaki ; FUKUDA Uina
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 血小板 / 肺発生 / CLEC-2 / podoplanin / TGF-β / myofibroblast / Podoplanin

Outline of Final Research Achievements

CLEC-2 deficiency in mice causes neonatal death by lung developmental abnormality and respiratory failure.These phenotypes were also seen in platelet-depleted fetuses and platelet-specific CLEC-2 deleted fetuses. we found that TGF-β in platelets and podoplanin (a CLEC-2 ligand) on lymphatic endothelial cells was important for CLEC-2-dependent lung development. These results suggest that interaction between platelet CLEC-2 and lymphatic endothelial cell podoplanin activates platelets and TGF-β released from activated platelets contributes normal lung development.

Academic Significance and Societal Importance of the Research Achievements

本課題において、血小板CLEC-2とリンパ管内皮Pdpnの相互作用が肺発生に必須であること、さらにその相互作用による血小板活性化とそれに伴って放出されるTGF-βが重要であることが明らかとなった。これまで、臓器発生はその臓器内の組織間相互作用や隣接する組織からの影響により進むと考えられてきた。本課題により示された、全身を流れる血球（血小板）が特定の臓器（肺）の発生に必須であるという事実は、これまでの臓器発生の考え方に新たなコンセプトを提示したと考えている。このような新しい生命現象の発見は、新たな研究領域の創生や疾患の治療戦略の開発につながる可能性があり、学術的、社会的意義は大きい。

Research Products

• [Journal Article] Platelets play an essential role in murine lung development through Clec-2/podoplanin interaction (2018)
  • Author(s): Tsukiji Nagaharu、Inoue Osamu、Morimoto Mitsuru、Tatsumi Norifumi、Nagatomo Hiroaki、Ueta Koji、Shirai Toshiaki、Sasaki Tomoyuki、Otake Shimon、Tamura Shogo、Tachibana Toshiaki、Okabe Masataka、Hirashima Masanori、Ozaki Yukio、Suzuki-Inoue Katsue
  • Journal Title: Blood Volume: 132 Issue: 11 Pages: 1167-1179
  • DOI: 10.1182/blood-2017-12-823369
  • Peer Reviewed
• [Journal Article] Cobalt hematoporphyrin inhibits CLEC-2?podoplanin interaction, tumor metastasis, and arterial/venous thrombosis in mice (2018)
  • Author(s): Tsukiji Nagaharu、Osada Makoto、Sasaki Tomoyuki、Shirai Toshiaki、Satoh Kaneo、Inoue Osamu、Umetani Norihiko、Mochizuki Chihiro、Saito Tamio、Kojima Soichi、Shinmori Hideyuki、Ozaki Yukio、Suzuki-Inoue Katsue
  • Journal Title: Blood Advances Volume: 2 Issue: 17 Pages: 2214-2225
  • DOI: 10.1182/bloodadvances.2018016261
  • Peer Reviewed / Open Access
• [Journal Article] Platelet CLEC-2: Roles Beyond Hemostasis (2018)
  • Author(s): Suzuki-Inoue, K. Tsukiji, N. Shirai, T. Osada, M. Inoue, O. Ozaki, Y.
  • Journal Title: Seminars in thrombosis and hemostasis Volume: 44 Issue: 02 Pages: 126-134
  • DOI: 10.1055/s-0037-1604090
  • Peer Reviewed
• [Journal Article] Platelet functions in development and regeneration (2017)
  • Author(s): 服部浩一
  • Journal Title: Japanese Journal of Thrombosis and Hemostasis Volume: 28 Issue: 5 Pages: 589-596
  • DOI: 10.2491/jjsth.28.589
  • NAID: 130006831909
  • ISSN: 0915-7441, 1880-8808
  • Peer Reviewed / Open Access
• [Journal Article] The platelet-activating receptor C-type lectin receptor-2 plays an essential role in liver regeneration after partial hepatectomy in mice. (2017)
  • Author(s): Kono H, Fujii H, Suzuki-Inoue K, Inoue O, Furuya S, Hirayama K, Akazawa Y, Nakata Y, Sun C, Tsukiji N, Shirai T, Ozaki Y
  • Journal Title: Journal of thrombosis and haemostasis Volume: 印刷中 Issue: 5 Pages: 1-11
  • DOI: 10.1111/jth.13672
  • Peer Reviewed
• [Presentation] リンパ管内皮Podoplaninと血小板CLEC-2の相互作用が関与する肺発生機構 (2018)
  • Author(s): 築地長治
  • Organizer: 日本リンパ学会
• [Presentation] 器官形成の新たなkey player血小板：肺発生における血小板CLEC-2の役割 (2018)
  • Author(s): 築地長治
  • Organizer: 日本血栓止血学会
  • Invited
• [Presentation] リンパ管内皮Podoplaninと血小板CLEC-2の相互作用が関与する肺発生機構 (2018)
  • Author(s): 築地長治、井上修、森本充、辰巳徳史、長友啓明、植田康司、白井俊光、佐々木知幸、大竹志門、田村彰吾、立花利公、岡部正隆、平島正則、尾崎由基男、井上克枝
  • Organizer: 日本リンパ学会
• [Presentation] Platelets as a novel key player in organogenesis: Clec-2/podoplanin interaction regulates fetal lung development. (2018)
  • Author(s): 築地長治、井上修、森本充、辰巳徳史、長友啓明、植田康司、白井俊光、佐々木知幸、大竹志門、田村彰吾、立花利公、岡部正隆、平島正則、尾崎由基男、井上克枝
  • Organizer: 日本血栓止血学会
  • Invited
• [Presentation] Platelet activation by CLEC-2-Podoplanin interaction is essential for lung development (2017)
  • Author(s): N. Tsukiji, O. Inoue, T. Shirai, S. Tamura, S. Otake, T. Sasaki, K. Satoh, Y. Ozaki, K. Suzuki-Inoue
  • Organizer: International Societyon Thrombosis and Haemostasis 2017 Congress
  • Place of Presentation: ドイツ ベルリン
  • Year and Date: 2017-07-08
  • Int'l Joint Research
• [Presentation] 血小板によるCLEC-2-Podoplaninシグナルを介した新たな肺胞形成メカニズム (2017)
  • Author(s): 築地長治, 井上修, 辰巳徳史, 岡部正隆, 森本充, 植田康司, 平島正則, 佐々木知幸, 白井俊光, 田村彰吾, 大竹志門, 佐藤金夫, 尾崎由基男, 井上克枝
  • Organizer: 第39回日本血栓止血学会
  • Place of Presentation: 愛知県 名古屋市
  • Year and Date: 2017-06-08
• [Presentation] 血小板によるCLEC-2-Podoplaninシグナルを介した新たな肺胞形成メカニズム (2017)
  • Author(s): 築地長治, 井上修, 辰巳徳史, 岡部正隆, 森本充, 植田康司, 平島正則, 佐々木知幸, 白井俊光, 田村彰吾, 大竹志門, 佐藤金夫, 尾崎由基男, 井上克枝
  • Organizer: 日本血栓止血学会
• [Presentation] Platelet activation by CLEC-2-Podoplanin interaction is essential for lung development (2017)
  • Author(s): N. Tsukiji, O. Inoue, T. Shirai, S. Tamura, S. Otake, T. Sasaki, K. Sato, Y. Ozaki, K. Suzuki-Inoue
  • Organizer: International Society on Thrombosis and Haemostasis
  • Int'l Joint Research
• [Presentation] 血小板CLEC-2は肺中皮細胞分化を介して呼吸機能獲得に寄与する (2016)
  • Author(s): 築地長治, 井上修, 田村彰吾, 白井俊光, 佐々木知幸, 佐藤金夫, 井上克枝, 尾崎由基男
  • Organizer: 第38回日本血栓止血学会
  • Place of Presentation: 奈良県 奈良市
  • Year and Date: 2016-06-16
• [Presentation] Clec-2 on platelets is essential for alveogenesis and respiratory function by regulating differentiation of lung mesothelial cells (2016)
  • Author(s): Nagaharu Tsukiji, Osamu Inoue, Norifumi Tatsumi, Mitsuru Morimoto, Shogo Tamura, Toshiaki Shirai, Tomoyuki Sasaki, Kaneo Sato, Masataka Okabe, Yukio Ozaki and Katsue Suzuki-Inoue
  • Organizer: JSDB Special Symposium: Frontier of Developmental Biology Hosted by JSDB
  • Place of Presentation: 東京都 文京区
• [Remarks] 山梨大学大学院総合研究部医学域臨床医学系臨床検査医学講座ホームページ
  • URL: http://www.med.yamanashi.ac.jp/clinical/clin0lab/