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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-02, Vol.110 (8), p.3023-3028
• Main Authors: Hiramoto, Takafumi, Ebihara, Yasuhiro, Mizoguchi, Yoko, Nakamura, Kazuhiro, Yamaguchi, Kiyoshi, Ueno, Kazuko, Nariai, Naoki, Mochizuki, Shinji, Yamamoto, Shohei, Nagasaki, Masao, Furukawa, Yoichi, Tani, Kenzaburo, Nakauchi, Hiromitsu, Kobayashi, Masao, Tsuji, Kohichiro
• Format: Article
• Language: English
• Subjects: Biological Sciences; Cell Differentiation - drug effects; Cell lines; Cultured cells; Dose-Response Relationship, Drug; Gene expression; Genetic disorders; Genetic mutation; Granulocyte Colony-Stimulating Factor - pharmacology; Hematopoietic stem cells; Humans; Induced pluripotent stem cells; Leukocyte Elastase - genetics; Messenger RNA; Mutation; Neutropenia; Neutropenia - congenital; Neutropenia - immunology; Neutropenia - pathology; Neutrophils; Neutrophils - cytology; Neutrophils - immunology; Pluripotent Stem Cells - immunology; Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Stem cells; Stromal cells; Wnt3A Protein - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1217039110

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.