Hematopoietic stem cell regulation by the Notch signaling-including hematopoietic stem cell induction from human embryonic stem cells-

Notch信号传导的造血干细胞调节——包括从人胚胎干细胞诱导造血干细胞——

基本信息

批准号：
17390274
负责人：
CHIBA Shigeru
金额：
$ 9.86万
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：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Notch signaling enables the hematopoietic stem cells (HSC) to expand ex vivo while maintaining their immaturity. It is, however, to be determined whether the Notch signaling plays an important role in the bone marrow niche for the self HSC renewal. In this project, we aimed at approaching this question by using mice variably lacking Notch1 and/or Notch2 genes or wild-type mice administered with YO01027, a Notch signaling inhibitor. First, we compared the absolute number of recovering Lin-Scal+cKit+ (LSK) cells or CD34-LSK cells in the bone marrow of Notchl+/-Notch2+/- mice after administration with 5-FU, or wild-type mice administered with 5-FU followed by the YO01027 administration. Contrary to our expectation, however, we were unable to find the difference in either kind of experiment, compared with the control mice, and thus, no proof was obtained supporting the hypothesis that Notch signaling plays a physiological role in the HSC maintenance in the bone marrow.The successful induction of HSC from human embryonic stem (ES) cells allows us to consider various applications of those HSC, such as the industrialized production of clinical use-oriented blood cells. In this project, we investigated whether the HSC could be generated from human ES cells, based on our previous finding that Notch signaling plays an important role in HSC generation during embryogenesis. We induced differentiation from a human ES cell line, KhES-3, and sorted ES cell-derived cells using various combinations of surface markers that potentially represent HSC, such as CD34, CD133, KDR, CD90, CD150, CD105, PCLP-1, PECAM1, and VE-Cadherin. Those that were sorted as such, however, showed the potential to differentiate into endothelial cells and macrophages, but we were unable to identify the cells showing remarkable hematopoietic actiity.

Notch信号传导使造血干细胞（HSC）在保持其不成熟的同时扩展了离体。但是，要确定Notch信号是否在自我HSC更新的骨髓细分市场中起重要作用。在这个项目中，我们旨在通过使用Notch1和/或Notch2基因或使用Notch信号抑制剂YO01027施用的Notch1和/或Notch2基因或野生型小鼠来解决这个问题。首先，我们比较了用5-FU或用5-FU给药后，我们比较了Notchl +/- notch2 +/-小鼠在Notchl +/- notch2 +/-小鼠骨髓中恢复的Lin-Scal+CKIT+（LSK）细胞的绝对数量或CD34-LSK细胞的绝对数量-fu之后是YO01027管理。然而，与我们的期望相反，与对照小鼠相比，我们无法找到两种实验的差异，因此，没有得到证明，证明了Notch信号在骨骼中HSC维持中起生理作用的假设骨髓。从人类胚胎干细胞（ES）细胞成功诱导HSC，使我们能够考虑这些HSC的各种应用，例如临床面向使用的血细胞的工业化产生。在这个项目中，我们根据我们以前的发现，即在胚胎发生过程中Notch信号传导在HSC产生中起重要作用，我们研究了HSC是否可以从人类ES细胞中产生。我们使用各种表面标记的组合诱导了与人ES细胞系KHES-3和分类的ES细胞衍生细胞的分化，这些标记可能代表HSC，例如CD34，CD133，KDR，CD90，CD90，CD150，CD150，CD1105，PCLP-1，PCLP-1，， PECAM1和VE-辅助蛋白。然而，那些被分类的人表明了分化为内皮细胞和巨噬细胞的潜力，但是我们无法鉴定出表现出显着的造血作用的细胞。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Antineoplastic effect of a single oral dose of the novel Flt3 inhibitor KRN383 on xenografted human leukemic cells harboring Flt3-activating mutations.

单剂量口服新型 Flt3 抑制剂 KRN383 对携带 Flt3 激活突变的异种移植人类白血病细胞的抗肿瘤作用。

DOI：
发表时间：
2006
期刊：
Leuk Res 30
影响因子：
0
作者：
Nishiyama U;et al.
通讯作者：
et al.

Miwa's Hematology (3rd edition) (Laboratory examination of hematopoietic stem cells)

三和血液学（第3版）（造血干细胞的实验室检查）

DOI：
发表时间：
2006
期刊：
影响因子：
0
作者：
Sanada M;Uike N;Ohyashiki K;Ozawa K;Lili W;Hangaishi A;Kanda Y;Chiba S;Kurokawa M;Omine M;Mitani K;Ogawa S.;Shigeru Chiba (co-author)
通讯作者：
Shigeru Chiba (co-author)

Bessatsu Igaku-no-Ayumi-Hematological disorders-State of arts Ver.3 (Notch signaling and hematopoietic cells)

Bessatsu Igaku-no-Ayumi-血液疾病-State of arts Ver.3（Notch信号传导和造血细胞）

DOI：
发表时间：
2005
期刊：
影响因子：
0
作者：
Sanada M;Uike N;Ohyashiki K;Ozawa K;Lili W;Hangaishi A;Kanda Y;Chiba S;Kurokawa M;Omine M;Mitani K;Ogawa S.;Shigeru Chiba (co-author);千葉滋(分担執筆);Shigeru Chiba (co-author)
通讯作者：
Shigeru Chiba (co-author)

Antineoplastic effect of a single oral dose of the novel Flt3 inhibitor KRN383 on xengrafted human leukemic cells harboring Flt3-activating mutations.

单剂量口服新型 Flt3 抑制剂 KRN383 对携带 Flt3 激活突变的异种移植人类白血病细胞的抗肿瘤作用。