Immortalization of Erythroblasts by c-MYC and BCL-XL Enables Large-Scale Erythrocyte Production from Human Pluripotent Stem Cells

• Hirose, Sho-ichi

• Takayama, Naoya

• Nakamura, Sou

• Nagasawa, Kazumichi

• Ochi, Kiyosumi

• Hirata, Shinji

• Yamazaki, Satoshi

• Yamaguchi, Tomoyuki

• Otsu, Makoto

• Sano, Shinya

• Takahashi, Nobuyasu

• Sawaguchi, Akira

• Ito, Mamoru

• Kato, Takashi

• Nakauchi, Hiromitsu

• Eto, Koji

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.

Journal

• Stem Cell Reports

  Stem Cell Reports 1 (6), 499-508, 2013-12

  Elsevier Inc.

Details

• CRID: 1050282810754704000
• NII Article ID: 120005350227
• ISSN: 22136711
• HANDLE: 2433/179558
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • CiNii Articles