title: Wnt3a stimulates maturation of impaired neutrophils developed from severe congenital neutropenia patient-derived pluripotent stem cells.
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 the maturation of SCN-iPS cell-derived neutrophils. These results indicate that SCN-iPS cells provide a useful disease model for SCN, and the activation of the Wnt3a/β-catenin pathway may offer a novel therapy for SCN with ELANE mutation.
authors: Division of Molecular and Clinical Genomics, Medical Institute of Bioregulation,  Kyushu University, Higashi-ku, Fukuoka 812-8582,  Japan.
authors: Takafumi
authors: T
authors: Hiramoto
authors: Yasuhiro
authors: Y
authors: Ebihara
authors: Yoko
authors: Y
authors: Mizoguchi
authors: Kazuhiro
authors: K
authors: Nakamura
authors: Kiyoshi
authors: K
authors: Yamaguchi
authors: Kazuko
authors: K
authors: Ueno
authors: Naoki
authors: N
authors: Nariai
authors: Shinji
authors: S
authors: Mochizuki
authors: Shohei
authors: S
authors: Yamamoto
authors: Masao
authors: M
authors: Nagasaki
authors: Yoichi
authors: Y
authors: Furukawa
authors: Kenzaburo
authors: K
authors: Tani
authors: Hiromitsu
authors: H
authors: Nakauchi
authors: Masao
authors: M
authors: Kobayashi
authors: Kohichiro
authors: K
authors: Tsuji
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D019272:Leukocyte Elastase / Q000235:genetics; D009154:Mutation; D009503:Neutropenia / Q000151:congenital / Q000276:immunology* / Q000473:pathology; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D039904:Pluripotent Stem Cells / Q000276:immunology*; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060509:Wnt3A Protein / Q000502:physiology*
chemical_list: C555510:WNT3A protein, human; D060509:Wnt3A Protein; D016179:Granulocyte Colony-Stimulating Factor; D019272:Leukocyte Elastase
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