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

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 Sugimoto, Atsushi Kaneda, Takuya Yamamoto, Hirohide Saito (), Naoya Takayama () and Koji Eto ()
Additional contact information
Si Jing Chen: Kyoto 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
Hirohide Saito: Kyoto University
Naoya Takayama: Chiba University
Koji Eto: Kyoto University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46605-0

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