Analysis of pathogenesis of congenital bone marrow failure syndrome and establishment of its treatment using human iPS cells

先天性骨髓衰竭综合征发病机制分析及人iPS细胞治疗方案的建立

• 批准号: 21390321
• 负责人: EBIHARA Yasuhiro
• 金额: $ 11.56万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21390321/
• 关键词: iPS細胞; 先天性骨髄不全症候群; 重症先天性好中球減少症; ダウン症候群; RUNX1; WNT3a; 好中球; 巨核球; 赤血球; Fanconi貧血; Kostmann症候群; Down症候群

1) Analysis of severe congenital neutropenia-derived iPS cells(SCN-iPS cells) Clonal hematopoietic assay indicated that SCN-iPS cells had a significantly decreased capability to generate neutrophil colonies, which contained few mature neutrophils, reflecting the feature of SCN. Since the expression of WNT/b-Catenin pathway-related genes were decreased, we added WNT3a to hematopoiesis-indunction culture. WNT3a stimulated the maturation of SCN-iPS cell-derived neutrophils. These results suggested the possibility of treatment of SCN using WNT3a.2) Analysis of Down syndrome-derived iPS cells(DS-iPS cells) Clonal hematopoietic assay indicated that DS-iPS cells had increased capabilities to generate all types of definitive hematopoietic/blood cells. Microarray analysis also demonstrated an increased expression of RUNX1 on chromosome 21, which was confirmed by RT-PCR. These results indicated that hematopoietic abnormalities in DS patients might relate with the increased expression of RUNX1, which could be a target gene for the treatment of hematopoietic disorders in patients with Down syndrome.

1)对重症先天性血小板减少症来源的iPS细胞（SCN-iPS细胞）的分析克隆造血试验表明，SCN-iPS细胞具有显著降低的产生中性粒细胞集落的能力，其包含很少的成熟中性粒细胞，反映了SCN的特征。由于WNT/b-Catenin通路相关基因的表达降低，我们将WNT 3a添加到造血抑制培养物中。WNT 3a刺激SCN-iPS细胞衍生的嗜中性粒细胞的成熟。这些结果表明使用WNT 3a治疗SCN的可能性。2）唐氏综合征衍生的iPS细胞（DS-iPS细胞）的分析克隆造血测定表明，DS-iPS细胞具有增加的产生所有类型的永久造血/血细胞的能力。微阵列分析也证实了RUNX 1在21号染色体上的表达增加，这通过RT-PCR证实。提示RUNX 1基因表达增高可能与DS患者的造血功能异常有关，RUNX 1基因可能是治疗Down综合征患者造血功能障碍的靶基因。

项目成果

Reduction of N-glycolylneuraminic acid in human induced pluripotent stem cells generated or cultured under feeder- and serum-free defined conditions.

• DOI: 10.1371/journal.pone.0014099
• 发表时间: 2010-11-23
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Hayashi Y;Chan T;Warashina M;Fukuda M;Ariizumi T;Okabayashi K;Takayama N;Otsu M;Eto K;Furue MK;Michiue T;Ohnuma K;Nakauchi H;Asashima M
• 通讯作者: Asashima M

Human ES cell-derived MSC maintining human ES and iPS cells under animal serum-free conditions

人 ES 细胞衍生的 MSC 在无动物血清条件下维持人 ES 和 iPS 细胞

• 发表时间: 2009
• 作者: Ebihara Y;Ma F;Hanada S;et al.
• 通讯作者: et al.

ヒト由来の多能性幹細胞を分化させる方法

人源多能干细胞的分化方法

• 发表时间: 2010

Hematopoiesis of human induced pluripotent stem cells derived from patients with Down syndrome

来自唐氏综合症患者的人类诱导多能干细胞的造血作用

• 发表时间: 2010
• 作者: Nishihama N;et al.
• 通讯作者: et al.

多能性幹細胞からの肥満細胞の製造方法

从多能干细胞产生肥大细胞的方法

• 发表时间: 2009