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A let-7 microRNA-RALB axis links the immune properties of iPSC-derived megakaryocytes with platelet producibility

Author

Listed:
  • Si Jing Chen

    (Kyoto University
    Chiba University)

  • Kazuya Hashimoto

    (Kyoto University)

  • Kosuke Fujio

    (Kyoto University)

  • Karin Hayashi

    (Kyoto University)

  • Sudip Kumar Paul

    (Chiba University)

  • Akinori Yuzuriha

    (Kyoto University)

  • Wei-Yin Qiu

    (Kyoto University)

  • Emiri Nakamura

    (Kyoto University)

  • Maria Alejandra Kanashiro

    (Chiba University)

  • Mio Kabata

    (Kyoto University)

  • Sou Nakamura

    (Kyoto University)

  • Naoshi Sugimoto

    (Kyoto University)

  • Atsushi Kaneda

    (Chiba University)

  • Takuya Yamamoto

    (Kyoto University
    Kyoto University
    RIKEN Center for Advanced Intelligence Project (AIP))

  • Hirohide Saito

    (Kyoto University)

  • Naoya Takayama

    (Chiba University)

  • Koji Eto

    (Kyoto University
    Chiba University)

Abstract

We recently achieved the first-in-human transfusion of induced pluripotent stem cell-derived platelets (iPSC-PLTs) as an alternative to standard transfusions, which are dependent on donors and therefore variable in supply. However, heterogeneity characterized by thrombopoiesis-biased or immune-biased megakaryocytes (MKs) continues to pose a bottleneck against the standardization of iPSC-PLT manufacturing. To address this problem, here we employ microRNA (miRNA) switch biotechnology to distinguish subpopulations of imMKCLs, the MK cell lines producing iPSC-PLTs. Upon miRNA switch-based screening, we find imMKCLs with lower let-7 activity exhibit an immune-skewed transcriptional signature. Notably, the low activity of let-7a-5p results in the upregulation of RAS like proto-oncogene B (RALB) expression, which is crucial for the lineage determination of immune-biased imMKCL subpopulations and leads to the activation of interferon-dependent signaling. The dysregulation of immune properties/subpopulations, along with the secretion of inflammatory cytokines, contributes to a decline in the quality of the whole imMKCL population.

Suggested Citation

  • Si Jing Chen & Kazuya Hashimoto & Kosuke Fujio & Karin Hayashi & Sudip Kumar Paul & Akinori Yuzuriha & Wei-Yin Qiu & Emiri Nakamura & Maria Alejandra Kanashiro & Mio Kabata & Sou Nakamura & Naoshi Sug, 2024. "A let-7 microRNA-RALB axis links the immune properties of iPSC-derived megakaryocytes with platelet producibility," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46605-0
    DOI: 10.1038/s41467-024-46605-0
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    References listed on IDEAS

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    1. Chao Yan & Degang Liu & Liwei Li & Michael F. Wempe & Sunny Guin & May Khanna & Jeremy Meier & Brenton Hoffman & Charles Owens & Christina L. Wysoczynski & Matthew D. Nitz & William E. Knabe & Mansoor, 2014. "Discovery and characterization of small molecules that target the GTPase Ral," Nature, Nature, vol. 515(7527), pages 443-447, November.
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