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July 02, 2025
Destabilizing microtubules to boost platelet production from iPS cell-derived megakaryocytes
Platelet transfusions are essential for managing thrombocytopenia and bleeding disorders, yet donor-derived platelets face limitations such as short shelf life, supply shortages, and immune incompatibility. To address these critical issues, the Eto Lab has developed imMKCLs—conditionally immortalized megakaryocyte lines derived from human iPS cells—which can be expanded and matured to produce functional platelets. However, platelet yields remain suboptimal under static culture conditions.
Using single-cell time-lapse imaging, the research team observed that imMKCLs exhibit asynchronous and heterogeneous platelet production, with only a minority of cells releasing large numbers of platelet-like particles (PLPs). A high-content chemical genetics screen identified MT-destabilizing agents, particularly vinca alkaloids such as vincristine (VCR), as potent enhancers of proplatelet extension formation. VCR treatment on day 3 of differentiation significantly increased PLP output, especially under turbulence-enhanced culture conditions using the VerMES™ bioreactor. These findings demonstrate that timed microtubule destabilization enhances platelet biogenesis from iPS cell-derived megakaryocytes without compromising function.
Further analysis revealed an inverse correlation between MT content and platelet yield. Compared to static cultures, imMKCLs cultured under turbulent flow showed reduced MT staining and higher platelet productivity. VCR addition further boosted yields, with optimal effects observed when applied on day 3, after polyploidization but before proplatelet formation. Early or late VCR treatment diminished efficacy, highlighting a critical time-window for intervention.
Importantly, platelets produced under VCR treatment retained key functional properties. Flow cytometry and confocal imaging confirmed responsiveness to activation agonists, low Annexin V binding, and the ability to spread on fibrinogen-coated surfaces. In vivo experiments using thrombocytopenic NSGS-SGM3 mice demonstrated that VCR-treated iPS cell-derived platelets restored hemostasis effectively, although higher VCR doses slightly reduced platelet persistence and marginal band structure.
This study underscores the role of MT dynamics in megakaryocyte maturation and platelet biogenesis. By leveraging FDA-approved compounds like VCR, the researchers present a practical method to enhance platelet yields from iPS cell-derived sources. These insights pave the way for scalable, cost-effective platelet production systems for transfusion medicine, with future work aimed at elucidating the underlying mechanism of MT modulation and its role during maturation.
Paper Details
- Journal: PLOS One
- Title: Association of microtubule destabilization with platelet yields in terminally differentiating hiPSC-derived megakaryocyte lines
- Authors: Emiri Nakamura1, Yasuo Harada1,2, Trevor Bingham3, Christian Skorik3,4, Anjali Jha3,5,
John Atwater3,6, Natsumi Higashi1, Kosuke Fujio1,2, Mariko Ishiguro1, Haruki Okamoto1, Leonard I. Zon3,
George Q. Daley3, Andrew L. Frelinger7, Koji Eto1, Thorsten M. Schlaeger3*
*: Corresponding author - Author Affiliations:
- Center for iPS Cell Research and Application (CiRA), Kyoto University
- Otsuka Pharmaceutical Co., Ltd.
- Boston Children's Hospital Stem Cell Program and Harvard Medical School
- STEMCELL Technologies
- Harvard T.H. Chan School of Public Health
- NYU Grossman School of Medicine
- Center for Platelet Research Studies at Boston Children's Hospital