Mechanism of turbulence mediated platelet biogenesis and application to ex vivo manufacturing of platelets

2021 Fiscal Year Final Research Report

• Project/Area Number: 18H04164
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 90:Biomedical engineering and related fields
• Research Institution: Kyoto University
• Principal Investigator: ETO KOJI 京都大学, iPS細胞研究所, 教授 (50286986)
• 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
• 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

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.

Free Research Field

生体医工学、血液学、血栓止血学、幹細胞生物学

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。