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- Title
A let-7 microRNA-RALB axis links the immune properties of iPSC-derived megakaryocytes with platelet producibility.
- Authors
Chen, Si Jing; Hashimoto, Kazuya; Fujio, Kosuke; Hayashi, Karin; Paul, Sudip Kumar; Yuzuriha, Akinori; Qiu, Wei-Yin; Nakamura, Emiri; Kanashiro, Maria Alejandra; Kabata, Mio; Nakamura, Sou; Sugimoto, Naoshi; Kaneda, Atsushi; Yamamoto, Takuya; Saito, Hirohide; Takayama, Naoya; Eto, Koji
- 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. The authors pioneered the iPSC-derived platelet transfusion in human. Here they employ miRNA switches, identifying RALB as a determinant of immune megakaryocytes and a marker for quality control, advancing standardization of iPSC-platelet production.
- Subjects
MEGAKARYOCYTES; BLOOD platelets; THROMBOPOIETIN receptors; BLOOD platelet transfusion; BIOMARKERS; QUALITY control
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-46605-0