Mechanism of turbulence mediated platelet biogenesis and application to ex vivo manufacturing of platelets
Project/Area Number |
18H04164
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Research Category |
Grant-in-Aid for Scientific Research (A)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Medium-sized Section 90:Biomedical engineering and related fields
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Research Institution | Kyoto University |
Principal Investigator |
ETO KOJI 京都大学, iPS細胞研究所, 教授 (50286986)
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Co-Investigator(Kenkyū-buntansha) |
中村 壮 京都大学, iPS細胞研究所, 特定拠点助教 (50769833)
|
Project Period (FY) |
2018-04-01 – 2021-03-31
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Project Status |
Completed (Fiscal Year 2021)
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Budget Amount *help |
¥44,460,000 (Direct Cost: ¥34,200,000、Indirect Cost: ¥10,260,000)
Fiscal Year 2020: ¥14,170,000 (Direct Cost: ¥10,900,000、Indirect Cost: ¥3,270,000)
Fiscal Year 2019: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
Fiscal Year 2018: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
|
Keywords | 血小板 / 巨核球 / iPS細胞 / 乱流 / せん断ずり応力 / バイオリアクター / ずり応力 / 乱流エネルギー / 細胞膜 / エンドペプチダーゼ / turbulence / shear stress |
Outline of Final Research Achievements |
Based on finding of a novel concept of turbulence in platelet biogenesis in vivo, we established a clinical scale ex vivo manufacturing system of bona fide type platelets from iPS cell-derived megakaryocyte cell lines, imMKCLs. Our in vivo observations within mouse BM clarified the crucial involvement of turbulent flow in platelet biogenesis. By identifying shear stress and turbulent energy as physical parameters for turbulence-dependent platelet generation, we dramatically improved the yield and quality of platelets, enabling to produce 100 billion intact platelets at 10L scale. As for potential mechanism in platelet biogenesis by turbulence, we proposed that CCL5, NRDC, IGFBP2, and MIF, released from mature imMKCLs following physical stimulation, might play crucial roles in remodeling of membrane in megakaryocyte maturation and platelet shedding. Subsequently, we also attempted to study the feasibility of large-scale manufacturing of platelets in 50L-scale turbulent-flow reactor.
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Academic Significance and Societal Importance of the Research Achievements |
血小板産生機構は、細胞質突起切断、巨核球細胞膜の不安定化断裂、細胞膜の連続的なbuddingなどの多様なシステムの使い分けの可能性が報告されている。その中で研究代表者らは、生体外製造人工血小板製造システムの開発とその臨床応用開発を進め、血小板産生のメカニズムに乱流物理条件が重要なことを発見し、血小板誕生機構解明における新たな概念を提唱した。その結果、巨核球をモデルとした細胞質肥大化、細胞膜リモデリング、膜切断の分子機構の詳細が今後明らかになると期待される。また、大規模な生体外での血小板製造開発を通じた社会実装への貢献も期待できる。
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Report
(5 results)
Research Products
(73 results)
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[Journal Article] The Effect of Megakaryocytes and Platelets Derived from Human-Induced Pluripotent Stem Cells on Bone Formation2021
Author(s)
Masashi Sato, Yasuhiro Shiga, Naoya Takayama, Masamitsu Sone, Kentaro Kosaka, Itsuro Motegi, Norichika Mizuki, Kazuhide Inage, Yawara Eguchi, Miyako Narita, Sumihisa Orita, Koji Eto, Seiji Ohtori
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Journal Title
Spine Surgery and Related Research
Volume: 5
Issue: 3
Pages: 196-204
DOI
NAID
ISSN
2432-261X
Year and Date
2021-05-27
Related Report
Peer Reviewed / Open Access
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[Journal Article] Fibroblasts from different body parts exhibit distinct phenotypes in adult progeria Werner syndrome2021
Author(s)
Kato H, Maezawa Y, Takayama N, Ouchi Y, Kaneko H, Kinoshita D, Takada-Watanabe A, Oshima M, Koshizaka M, Ogata H, Kubota Y, Mitsukawa N, Eto K, Iwama A, Yokote K.
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Journal Title
Aging (Albany NY)
Volume: 13
Issue: 4
Pages: 4946-4961
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] iPSC-Derived Platelets Depleted of HLA Class I Are Inert to Anti-HLA Class I and Natural Killer Cell Immunity.2020
Author(s)
Suzuki D, Flahou C, Yoshikawa N, Stirblyte I, Hayashi Y, Sawaguchi A, Akasaka M, Nakamura S, Higashi N, Xu H, Matsumoto T, Fujio K, Manz MG, Hotta A, Takizawa H, Eto K, Sugimoto N.
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Journal Title
Stem Cell Reports.
Volume: 14
Issue: 1
Pages: 49-59
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Suppressive effects of anagrelide on cell cycle progression and the maturation of megakaryocyte progenitor cell lines in human induced pluripotent stem cells2020
Author(s)
Takaishi K, Takeuchi M, Tsukamoto S, Takayama N, Oshima M, Kimura K, Isshiki Y, Kayamori K, Hino Y, Oshima-Hasegawa N, Mitsukawa S, Takeda Y, Mimura N, Ohwada C, Iseki T, Nakamura S, Eto K, Iwama A, Yokote K, Nakaseko C, Sakaida E
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Journal Title
Haematologica
Volume: 105
Issue: 5
Related Report
Peer Reviewed / Open Access
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[Journal Article] Suppressive effects of anagrelide on cell cycle progression and the maturation of megakaryocyte progenitor cell lines in human induced pluripotent stem cells.2019
Author(s)
Takaishi K, Takeuchi M, Tsukamoto S, Takayama N, Oshima M, Kimura K, Isshiki Y, Kayamori K, Hino Y, Oshima-Hasegawa N, Mitsukawa S, Takeda Y, Mimura N, Ohwada C, Iseki T, Nakamura S, Eto K, Iwama A, Yokote K, Nakaseko C, Sakaida E.
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Journal Title
Haematologica.
Volume: Sep 5
Issue: 5
Pages: 00-00
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome2018
Author(s)
Toki Tsutomu、Yoshida Kenichi、Wang RuNan、Okuno Yusuke、Kataoka Keisuke、Shiraishi Yuichi、Ohga Shouichi、Kuramitsu Madoka、Hamaguchi Isao、Ohara Akira、Kanno Hitoshi、Miyano Satoru、Kojima Seiji、Ishiguro Akira、Sugita Kanji、Kenmochi Naoya、Takahashi Satoru、Eto Koji、Ogawa Seishi、Ito Etsuro
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Journal Title
The American Journal of Human Genetics
Volume: 103
Issue: 3
Pages: 440-447
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Tyrosyl-tRNA synthetase stimulates thrombo103oietin-independent hematopoiesis accelerating recovery from thrombocytopenia2018
Author(s)
Kanaji T, Vo MN, Kanaji S, Zarpellon A, Shapiro R, Morodomi Y, Yuzuriha A, Eto K, Belani R, Do MH, Yang XL, Ruggeri ZM, Schimmel P
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Journal Title
Proceedings of the National Academy of Sciences, USA
Volume: 115(35)
Issue: 35
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] A β1-tubulin-based megakaryocyte maturation reporter system identifies novel drugs that promote platelet production2018
Author(s)
Seo H, Chen SJ, Hashimoto K, Endo H, Nishi Y, Ohta A, Yamamoto T, Hotta A, Akira Sawaguchi A, Hayashi H, Koseki N, Murphy GJ, Fukuda K, Sugimoto N, Eto K.
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Journal Title
Blood Advances
Volume: 2(17)
Issue: 17
Pages: 2262-2272
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Turbulence Activates Platelet Biogenesis to Enable Clinical Scale Ex Vivo Production.2018
Author(s)
Ito Y, Nakamura S, Sugimoto N, Shigemori T, Kato Y, Ohno M, Sakuma S, Ito K, Kumon H, Hirose H, Okamoto H, Nogawa M, Iwasaki M, Kihara S, Fujio K, Matsumoto T, Higashi N, Hashimoto K, Sawaguchi A, Harimoto KI, Nakagawa M, Yamamoto T, Handa M, Watanabe N, Nishi E, Arai F, Nishimura S, Eto K.
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Journal Title
Cell
Volume: 174(3)
Issue: 3
Pages: 636-648
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Skewed megakaryopoiesis in human induced pluripotent stem cell-derived haematopoietic progenitor cells harbouring calreticulin mutations2018
Author(s)
Hiraku Takei, Yoko Edahiro, Shuichi Mano, Nami Masubuchi, Yoshihsa Mizukami, Misa Imai, Soji Morishita, Kyohei Misawa, Tomonori Ochiai, Satoshi Tsuneda, Hiroshi Endo, Sou Nakamura, Koji Eto, Akimichi Ohsaka, Marito Araki, Norio Komatsu
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Journal Title
British Journal of Haematology
Volume: 印刷中
Issue: 6
Pages: 791-802
DOI
Related Report
Peer Reviewed
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[Presentation] 自家iPS細胞由来血小板の臨床研究(iPLAT1)の経過報告2020
Author(s)
諫田淳也, 杉本直志, 中村壮, 北野俊行, 菱澤方勝, 近藤忠一, 清水伸, 重政亜紀子, 平位秀世, 南学, 渡邊直英, 野川誠之, 半田誠, 岡本真一郎, 谷慶彦, 江藤浩之, 高折晃史
Organizer
第82回日本血液学会学術集会プレナリーセッション, 京都
Related Report
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