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Attempt to induce hematoopoietic stem cells from hemangioblasts

尝试从成血管细胞诱导造血干细胞

基本信息

批准号：
11470206
负责人：
HARA Takahiko
金额：
$ 8.64万
依托单位：
Tokyo Metropolitan Organization For Medical Research, The Tokyo Metropolitan Institute of Medical Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470206/
关键词：
AGM region hemangioblast PCLP1 AML1 c-myb hematopoietic stem cells endothelial cells stem cell plasticity Runix-1

项目摘要

Hematopoietic stem cells are known to be derived from hemangioblasts, common precursor cells for blood and endothelial cells. We have identified podocalyxin-like protein 1 (PCLP1) as a novel hemangioblast marker. PCLP1+CD45-cells in the AGM region are differentiated to hematopoietic cells and endothelial cells in vitro. When these cells were transplanted into busulfan-treated neonatal mice, they gave rise to hematopoietic stem cells (HSCs) as well as endothelial cells, smooth muscle cells, and stromal cells in lung, small intestine, and uterus. By retrovirus marking of stem cells in the AGM region, we proved that blood cells and vascular cells in small intestine are derived from single stem cells. Similar in vivo differentiation capacity was detected in the bone marrow CD45-positive side population, which are highly enriched for HSCs. Therefore, it is likely that hemangioblasts in the AGM region generated HSCs that are in turn transdifferentiated to non-hematopoietic cells in vivo.We have shown that two transcription factors, AMI-1 and c-myb, are essential for the generation of HSCs in the AGM region. To know functions of these proteins, we newly established immortalized cell lines from the AGM regions of knockout mice ofAMI-1 or c-myb genes. Then we reintroduced missing genes by taking advantage of inducible promoter. Gene expression studies revealed that mRNA for insulin-like growth factor binding protein-3 is suppressed by AML1.Further search of down stream effectors of AML-1 and c-myb would clarify the molecular mechanism of HSC development from hemangioblasts in the AGM region.

已知造血干细胞来源于成血管细胞、血液和内皮细胞的常见前体细胞。我们已经确定足萼蛋白样蛋白1（PCLP 1）作为一种新的成血管细胞标志物。AGM区的PCLP 1 + CD 45-细胞在体外分化为造血细胞和内皮细胞。当这些细胞被移植到白消安处理的新生小鼠，他们产生造血干细胞（HSC）以及内皮细胞，平滑肌细胞和基质细胞在肺，小肠和子宫。通过逆转录病毒标记AGM区的干细胞，证实了小肠血细胞和血管细胞均来源于单个干细胞。在骨髓CD 45阳性侧群中检测到类似的体内分化能力，其高度富集HSC。因此，这是可能的，在AGM区域的成血管细胞产生的HSC，反过来转分化为非造血cells in vivo.We已经表明，两个转录因子，AMI-1和c-myb，是必不可少的AGM区域的HSC的产生。为了了解这些蛋白质的功能，我们从AMI-1或c-myb基因敲除小鼠的AGM区建立了永生化细胞系。然后利用诱导型启动子重新导入缺失基因。基因表达研究表明，AML 1抑制胰岛素样生长因子结合蛋白-3（IGF-BBP-3）的mRNA表达。进一步研究AML-1和c-myb的下游效应子，将有助于阐明AGM区成血管细胞向HSC分化的分子机制。