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Function of transcription factors in hematopoietic differentiation

转录因子在造血分化中的作用

基本信息

批准号：
16390277
负责人：
NAKANO Toru
金额：
$ 9.15万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390277/
关键词：
cell differentiation stem cell hematopoiesis transcription factor embryonic stem cell reprograming GATA-1 Runx-1 造血システム

项目摘要

Blood cells are produced immature hematopoietic cells through commitment and maturation. Gene targeting analyses have revealed that various transcription factors are involved in the process. However, molecular functions of the factors remain unclear. In this stud, using the combination of in vitro differentiation from mouse embryonic stem cells (ES cells) to blood cells on OP9 stroma cells (OP9 system), and loss or gain of function of the transcription factors, roles of the factors such as GATA-1, GATA-2, Runx-1, and FOG-1 were analyzed.All of the factors examined showed that their functions on hematopoietic differentiation was dependent on the context of the cell diffrentiation. In other words, individual transcription factors and co-factors' function was different at different differentiation stages. For example, erythroid specific transcription factor, GATA-1, was essential for proliferation and differentiation at early and late erthropoiesis, respectively.One notable result is the self-renewal and multi-lineage differentiation ability of GATA-1 null proerythroblasts. We found that GATA-1-null proerythroblasts could survive and proliferate on OP9 stroma cells in the presence of erythropoietin. Furthermore, myeloid and mast cells were induced from the GATA-1-null proerythroblasts by the stimulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), respectively, but lymphoid differentiation was not achieved by in vivo transfer. Thus, without activity of the transcription factor required for terminal differentiation, even relatively mature and committed cells proliferate continuously with the differentiation capacity to other lineages. This data suggest that GATA-1 is a critical transcription factor to fix erythroid progenitors to the erythroid lineage.

血细胞是通过定型和成熟产生的未成熟造血细胞。基因靶向分析表明，各种转录因子参与了这一过程。然而，这些因子的分子功能仍不清楚。在这项研究中，使用体外分化的小鼠胚胎干细胞，（ES细胞）转化为0 P9基质细胞上的血细胞（OP 9系统），以及转录因子功能的丧失或获得，诸如加塔-1，加塔-2，Runx-1，和雾-结果表明，这些因子在造血分化中的作用依赖于细胞的环境分化也就是说，在不同的分化阶段，单个转录因子和辅助因子的功能是不同的。例如，红系特异性转录因子加塔-1分别在红细胞生成早期和晚期的增殖和分化中是必需的，一个显著的结果是加塔-1缺失的原成红细胞的自我更新和多谱系分化能力。我们发现，加塔-1-null proerythroblasts可以生存和增殖的OP 9基质细胞在促红细胞生成素的存在。此外，骨髓和肥大细胞诱导从加塔-1-null原成红细胞的刺激粒细胞-巨噬细胞集落刺激因子（GM-CSF）和白细胞介素-3（IL-3），分别，但淋巴样分化不能通过体内转移实现。因此，在没有终末分化所需的转录因子活性的情况下，即使相对成熟和定向的细胞也会连续增殖，并具有向其他谱系分化的能力。这些数据表明，加塔-1是将红系祖细胞固定到红系谱系的关键转录因子。