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Functional analyzes for common receptor tyrosine kinases of hematopoietic stem cells and vascular endothelial cells

造血干细胞和血管内皮细胞共同受体酪氨酸激酶的功能分析

基本信息

批准号：
08457279
负责人：
SUDA Toshio
金额：
$ 4.74万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457279/
关键词：
AGM region Hemangioblast Angiopoietin TEK 血液幹細胞血管内皮細胞 TIE アンギオポエチレン

项目摘要

Association between hematopoietic stem cells and their microenvironment are central to the development and maintenance of a functional hematopoietic system. The TEK receptor tyrosine kinase and its ligands angiopoietin-1 and -2 have been documented to be involved in the formation of the embryonic vasculature. Although the defect of vasuculo-angiogenesis was confirmed in both knockout mice of TEK and angiopoietin-1, the precise function of these molecules has not been well understood. Here, we evaluated the expression and function of TEK during embryogenesis, especially in the AGM (aorta-gonad-mesonephros) region, omphalo-mesenteric artery and vitelline artery, where definitive hematopoiesis newly takes place. In the vitelline artery at E9.5, TEK^+ hematopoietic cells aggregated each other and adhered to TEK^+ endothelial cells. Definitive hematopoiesis was not detected in TEK-deficient embryo. Soluble TEK protein inhibited the development of hematopoiesis and angiogenesis in AGM explant culture, and TEK knockout mice showed severely impaired definitive hematopoiesis. In vitro study, we found a novel function of angiopoietin-1 and -2 which promote expressing TEK cells to adhere to fibronectin and to aggregate each other. Finally, we showed that supplement of VEGF in the presence of angiopoietins promoted the proliferation of both hematopoietic cells and endothelial cells. These data provide a new regulatory system of the development and maintenance of definitive hematopoiesis through interaction with microenvironment.

造血干细胞与其微环境之间的关联对于功能性造血系统的发育和维持至关重要。TEK受体酪氨酸激酶及其配体血管生成素-1和-2已被证明参与胚胎脉管系统的形成。虽然在TEK和血管生成素-1基因敲除小鼠中证实了血管生成的缺陷，但这些分子的确切功能尚未得到很好的理解。在这里，我们评估了TEK在胚胎发生过程中的表达和功能，特别是在AGM（腹-性腺-中肾）区域，网膜-肠系膜动脉和卵黄动脉，其中确定的造血新发生。在E9.5的卵黄动脉中，TEK^+造血细胞相互聚集并粘附于TEK^+内皮细胞。TEK缺陷胚胎未检测到造血功能异常。可溶性TEK蛋白抑制AGM外植体培养中的造血和血管生成的发展，TEK敲除小鼠表现出严重受损的永久性造血。在体外研究中，我们发现了促血管生成素-1和-2的一种新功能，即促进表达TEK的细胞与纤维连接蛋白的粘附和相互聚集。最后，我们发现，在血管生成素的存在下补充VEGF促进造血细胞和内皮细胞的增殖。这些数据提供了一个新的调控系统的发展和维持确定的造血通过相互作用的微环境。