Identification of genes which are involved in the development and transdifferentiation of hematopoietic stem cells

鉴定参与造血干细胞发育和转分化的基因

基本信息

批准号：
15390308
负责人：
HARA Takahiko
金额：
$ 8.96万
依托单位：
TOKYO METROPOLITAN ORGANIZATION FOR MEDICAL RESEARCH
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390308/
关键词：
Hematopoietic stem cells AGM region Transdifferentiation Bone marrow stem cells Blood cells Hematopoietic development Gene 発生

项目摘要

In this investigation, we attempted to elucidate how hematopoietic stem cells are developed from AGM region of mouse embryos, and which factors are involved in the recruitment of bone marrow stem cells to injured organs First, we identified a set of genes which are expressed in purified bone marrow-derived hematopoietic stem cells, but not in hemangioblasts derived from differentiated ES cells. They included SHP1, c-mpl, Norel, and unknown gene S76. S76 mRNA is predominantly expressed in hematopoietic tissues in adult mice and encoded a membrane protein. RNAi mediated r repression of S76 mRNA in hematopoietic progenitor cells inhibited their growth, and augmented proliferative capacity of mast cell line, suggesting that S76 could be a novel regulator of cytokine-responsiveness in blood cells. On the other hand, we identified a novel protease RAMP and chemokine BRAY, both of which are up-regulated in muscular dystrophy mutant mice, mdx. RAMP and BRAK are expressed in skeletal muscle and brain, and associated in the process of muscle regeneration. In order to clarify in vivo roles of these secreted proteins, we newly generated transgenic and knock-out mouse lines. In addition to above described researches, we discovered novel roles of Meis3 and Runx1, and performed gene profiling studies of ovary and uterus, naturally-remodeling tissues. Although we only obtained clues, future studies by using genetically modified mice would provide a new paradigm for the development and transdifferentiation of hematopoietic stem cells.

在这项研究中，我们试图阐明造血干细胞是如何从小鼠胚胎的 AGM 区域发育而来，以及哪些因素参与将骨髓干细胞募集到受损器官中。骨髓来源的造血干细胞，但分化的 ES 细胞衍生的成血管细胞则不然。它们包括 SHP1、c-mpl、Norel 和未知基因 S76。 S76 mRNA 主要在成年小鼠的造血组织中表达并编码膜蛋白。 RNAi 介导的造血祖细胞中 S76 mRNA 的 r 抑制抑制了其生长，并增强了肥大细胞系的增殖能力，表明 S76 可能是血细胞中细胞因子反应性的新型调节剂。另一方面，我们发现了一种新的蛋白酶 RAMP 和趋化因子 BRAY，这两种酶在肌营养不良症突变小鼠 mdx 中均上调。 RAMP和BRAK在骨骼肌和大脑中表达，并与肌肉再生过程相关。为了阐明这些分泌蛋白的体内作用，我们新产生了转基因和敲除小鼠品系。除了上述研究之外，我们还发现了 Meis3 和 Runx1 的新作用，并对卵巢和子宫、自然重塑组织进行了基因分析研究。虽然我们只获得了线索，但未来使用转基因小鼠的研究将为造血干细胞的发育和转分化提供新的范例。