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Stem Cell Reports. 2013 Dec 5;1(6):499-508. doi: 10.1016/j.stemcr.2013.10.010. eCollection 2013.

Immortalization of erythroblasts by c-MYC and BCL-XL enables large-scale erythrocyte production from human pluripotent stem cells.

Author information

1
Laboratory of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
2
Laboratory of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan ; Clinical Application Department, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
3
Graduate School of Advanced Science and Engineering, Center for Advanced Life and Medical Science, Waseda University, Tokyo 162-8480, Japan.
4
Clinical Application Department, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
5
Department of Anatomy, Ultrastructural Cell Biology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
6
Central Institute for Experimental Animals, Kawasaki 210-0821, Japan.

Abstract

The lack of knowledge about the mechanism of erythrocyte biogenesis through self-replication makes the in vitro generation of large quantities of cells difficult. We show that transduction of c-MYC and BCL-XL into multipotent hematopoietic progenitor cells derived from pluripotent stem cells and gene overexpression enable sustained exponential self-replication of glycophorin A(+) erythroblasts, which we term immortalized erythrocyte progenitor cells (imERYPCs). In an inducible expression system, turning off the overexpression of c-MYC and BCL-XL enabled imERYPCs to mature with chromatin condensation and reduced cell size, hemoglobin synthesis, downregulation of GCN5, upregulation of GATA1, and endogenous BCL-XL and RAF1, all of which appeared to recapitulate normal erythropoiesis. imERYPCs mostly displayed fetal-type hemoglobin and normal oxygen dissociation in vitro and circulation in immunodeficient mice following transfusion. Using critical factors to induce imERYPCs provides a model of erythrocyte biogenesis that could potentially contribute to a stable supply of erythrocytes for donor-independent transfusion.

PMID:
24371805
PMCID:
PMC3871399
DOI:
10.1016/j.stemcr.2013.10.010
[Indexed for MEDLINE]
Free PMC Article
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