Expandable Megakaryocyte Cell Lines Enable Clinically Applicable Generation of Platelets from Human Induced Pluripotent Stem Cells

The donor-dependent supply of platelets is frequently insufficient to meet transfusion needs. To address this issue, we developed a clinically applicable strategy for the derivation of functional platelets from human pluripotent stem cells (PSCs). This approach involves the establishment of stable i...

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Bibliographic Details
Published in:Cell stem cell 2014-04, Vol.14 (4), p.535-548
Main Authors: Nakamura, Sou, Takayama, Naoya, Hirata, Shinji, Seo, Hideya, Endo, Hiroshi, Ochi, Kiyosumi, Fujita, Ken-ichi, Koike, Tomo, Harimoto, Ken-ichi, Dohda, Takeaki, Watanabe, Akira, Okita, Keisuke, Takahashi, Nobuyasu, Sawaguchi, Akira, Yamanaka, Shinya, Nakauchi, Hiromitsu, Nishimura, Satoshi, Eto, Koji
Format: Article
Language:English
Subjects:
Animals
bcl-X Protein - metabolism
Blood Platelets - cytology
Blood Platelets - metabolism
Cell Differentiation
Cells, Cultured
Disease Models, Animal
Embryonic Stem Cells - cytology
Embryonic Stem Cells - metabolism
Flow Cytometry
Humans
Induced Pluripotent Stem Cells - cytology
Induced Pluripotent Stem Cells - metabolism
Megakaryocytes - cytology
Megakaryocytes - metabolism
Mice
Mice, Inbred NOD
Mice, SCID
Polycomb Repressive Complex 1 - metabolism
Proto-Oncogene Proteins c-myc - metabolism
Thrombocytopenia - metabolism
Thrombocytopenia - pathology
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Summary:The donor-dependent supply of platelets is frequently insufficient to meet transfusion needs. To address this issue, we developed a clinically applicable strategy for the derivation of functional platelets from human pluripotent stem cells (PSCs). This approach involves the establishment of stable immortalized megakaryocyte progenitor cell lines (imMKCLs) from PSC-derived hematopoietic progenitors through the overexpression of BMI1 and BCL-XL to respectively suppress senescence and apoptosis and the constrained overexpression of c-MYC to promote proliferation. The resulting imMKCLs can be expanded in culture over extended periods (4–5 months), even after cryopreservation. Halting the overexpression of c-MYC, BMI1, and BCL-XL in growing imMKCLs led to the production of CD42b+ platelets with functionality comparable to that of native platelets on the basis of a range of assays in vitro and in vivo. The combination of robust expansion capacity and efficient platelet production means that appropriately selected imMKCL clones represent a potentially inexhaustible source of hPSC-derived platelets for clinical application. [Display omitted] •Expandable megakaryocyte progenitors were established from human PSCs•BMI1 and BCL-XL suppress senescence and apoptosis induced by c-MYC in imMKCLs•imMKCLs differentiate into mature megakaryocytes and release functional platelets•Rapid and efficient platelet yield provides key advantages for clinical application This study describes a clinically applicable strategy for the derivation of functional platelets from human induced pluripotent stem cells (iPSCs) using the establishment of stable immortalized megakaryocyte progenitor lines from the iPSCs.
ISSN:1934-5909
1875-9777
DOI:10.1016/j.stem.2014.01.011