2025-07-02 京都大学iPS細胞研究所
図1 微小管脱重合を促進する化合物がプロプレートレットを増加させる
<関連情報>
- https://www.cira.kyoto-u.ac.jp/j/pressrelease/news/250702-100000.html
- https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0326165
hiPSC由来巨核球終末分化株における微小管不安定化と血小板収率の関連性 Association of microtubule destabilization with platelet yields in terminally differentiating hiPSC-derived megakaryocyte lines
Emiri Nakamura,Yasuo Harada,Trevor Bingham,Christian Skorik,Anjali Jha,John Atwater,Natsumi Higashi,Kosuke Fujio,Mariko Ishiguro,Haruki Okamoto,Leonard I. Zon,George Q. Daley,Andrew L. Frelinger,Koji Eto,Thorsten M. Schlaeger
PLOS One Published: June 25, 2025
DOI:https://doi.org/10.1371/journal.pone.0326165
Abstract
Millions of platelet units are needed each year to manage thrombocytopenia and other conditions linked to excessive bleeding. These life-saving treatments still depend entirely on donated platelets, despite the numerous shortcomings associated with them, such as limited shelf life, supply shortages, unpredictable functionality, potential for infection, as well as immune-incompatibility issues. These challenges could be overcome with universal donor platelets generated from human induced pluripotent stem cell (hiPSC)-derived megakaryocytes (MKs). We recently developed expandable hiPSC-derived megakaryocytic cell lines (imMKCLs) as a potentially unlimited source for platelet production. imMKCL-derived platelets are functional and have already been tested in patients. In this study, we demonstrate through single-cell time-course imaging that imMKCL maturation is heterogeneous and asynchronous, with only a few imMKCLs generating platelets at any given time under static culture conditions. Using a chemical screen, we identify microtubule (MT) destabilizing agents, including vincristine (VCR), as promising hits, with a larger proportion of VCR-exposed imMKCLs developing proplatelet extensions and more platelets being produced per imMKCL. VCR use reduces the MT content of imMKCLs and results in the production of platelets with a diminished peripheral MT ring structure. Nevertheless, these platelets are functional, as evidenced by their normal response to agonists, their ability to attach to and spread on fibrinogen-coated surfaces, and their capacity to restore hemostasis in vivo. Interestingly, we also observed a negative correlation between the MT content of imMKCLs and platelet yields when we compared imMKCLs differentiated under static conditions (MThigh, low yield) to our turbulence-optimized VerMES™ bioreactor (MTlow, high yield). Taken together, our findings highlight the importance of MT dynamics in megakaryocyte biology, provide a possible explanation for the still poorly understood link between vinca alkaloid in vivo use and thrombocytosis, and bring us closer to realizing the clinical potential of affordable, off-the-shelf hiPSC-derived platelets.
