Wnt3a stimulates maturation of impaired neutrophils developed from severe congenital neutropenia patient-derived pluripotent stem cells

Takafumi Hiramoto, Yasuhiro Ebihara, Yoko Mizoguchi, Kazuhiro Nakamura, Kiyoshi Yamaguchi, Kazuko Ueno, Naoki Nariai, Shinji Mochizuki, Shohei Yamamoto, Masao Nagasaki, Yoichi Furukawa, Kenzaburo Tani, Hiromitsu Nakauchi, Masao Kobayashi, Kohichiro Tsuji

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

The derivation of induced pluripotent stem (iPS) cells from individuals of genetic disorders offers new opportunities for basic research into these diseases and the development of therapeutic compounds. Severe congenital neutropenia (SCN) is a serious disorder characterized by severe neutropenia at birth. SCN is associated with heterozygous mutations in the neutrophil elastase [elastase, neutrophil-expressed (ELANE)] gene, but the mechanisms that disrupt neutrophil development have not yet been clarified because of the current lack of an appropriate disease model. Here, we generated iPS cells from an individual with SCN (SCN-iPS cells). Granulopoiesis from SCN-iPS cells revealed neutrophil maturation arrest and little sensitivity to granulocyte-colony stimulating factor, reflecting a disease status of SCN. Molecular analysis of the granulopoiesis from the SCN-iPS cells vs. control iPS cells showed reduced expression of genes related to the wingless-type mmtv integration site family, member 3a (Wnt3a)/β-catenin pathway [e.g., lymphoid enhancer-binding factor 1], whereas Wnt3a administration induced elevation lymphoid enhancer-binding factor 1-expression and thematuration of SCN-iPS cell-derived neutrophils. These results indicate that SCN-iPS cells provide a useful disease model for SCN, and the activation of theWnt3a/β-catenin pathway may offer a novel therapy for SCN with ELANE mutation.

Original languageEnglish
Pages (from-to)3023-3028
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number8
DOIs
Publication statusPublished - 2013 Feb 19

Keywords

  • Apoptosis
  • SCN disease model
  • Unfolded protein response

ASJC Scopus subject areas

  • General

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