TY - JOUR
T1 - Wnt3a stimulates maturation of impaired neutrophils developed from severe congenital neutropenia patient-derived pluripotent stem cells
AU - Hiramoto, Takafumi
AU - Ebihara, Yasuhiro
AU - Mizoguchi, Yoko
AU - Nakamura, Kazuhiro
AU - Yamaguchi, Kiyoshi
AU - Ueno, Kazuko
AU - Nariai, Naoki
AU - Mochizuki, Shinji
AU - Yamamoto, Shohei
AU - Nagasaki, Masao
AU - Furukawa, Yoichi
AU - Tani, Kenzaburo
AU - Nakauchi, Hiromitsu
AU - Kobayashi, Masao
AU - Tsuji, Kohichiro
PY - 2013/2/19
Y1 - 2013/2/19
N2 - 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.
AB - 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.
KW - Apoptosis
KW - SCN disease model
KW - Unfolded protein response
UR - http://www.scopus.com/inward/record.url?scp=84874256711&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84874256711&partnerID=8YFLogxK
U2 - 10.1073/pnas.1217039110
DO - 10.1073/pnas.1217039110
M3 - Article
C2 - 23382209
AN - SCOPUS:84874256711
VL - 110
SP - 3023
EP - 3028
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 8
ER -