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Role for growth factors and extracellular matrixes in controlling hepatic stem cell differentiation

生长因子和细胞外基质在控制肝干细胞分化中的作用

基本信息

批准号：
12557096
负责人：
TANIGUCHI Hideki
金额：
$ 6.27万
依托单位：
Yokohama City University (2002)University of Tsukuba (2000-2001)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557096/
关键词：
cell growth differentiation cytokines 肝臓再生幹細胞再生医学

项目摘要

In the liver development, a number of growth factors (GFs) and extracellular matrixes (ECMs) lead to differentiation of the liver parenchymal cells. However, since the liver contains cells of many type, it is difficult to investigate their functional effects on hepatic stem cell population specifically. Prospective isolation and clonal assays for hepatic stem cells enable to examine direct effects of GFs and ECMs on such cell fraction. Using previously purified cells that fulfill the criteria for hepatic stem cells, we examined in this study how GFs and ECMs regulate their differentiation in the developing liver. We show here that HGF induced early transition of albumin (ALB)-negative stem cells to Alb-positive hepatic precursors regarding hepatoblasts, and then OSM promoted secondary their differentiation to finally tryptophan-2, 3-dioxygenase (TO)-positive mature hepatocytes. During such transition, ECMs are necessary for the differentiation of stem cells and precursors, but their effects are just supportive for them. In the first step of stem cell differentiation induced by HGF, the expression of CCAAT/enhancer birding protein (C/EBP), a basic leucine zipper protein of transcriptional factors, changed dramatically, and when the function of C/EBPs is inhibited in the stem cells, they stop turning to hepatocytes -lineage cells and proliferate actively. Those evidences are first findings to clear the mechanism of hepatic stem cell differentiation in the liver development.

在肝脏发育过程中，许多生长因子（GF）和细胞外基质（ECM）导致肝实质细胞的分化。然而，由于肝脏含有多种类型的细胞，很难研究它们对肝干细胞群的功能影响。肝干细胞的前瞻性分离和克隆测定使得能够检查GF和ECM对此类细胞部分的直接影响。使用先前纯化的符合肝干细胞标准的细胞，我们在这项研究中研究了GF和ECM如何调节它们在发育中的肝脏中的分化。我们在这里显示，肝细胞生长因子诱导白蛋白（ALB）阴性的干细胞的早期过渡到ALB阳性的肝前体细胞有关肝母细胞，然后OSM促进二次分化，最终色氨酸-2，3-双加氧酶（TO）阳性的成熟肝细胞。在这种转变过程中，ECM对于干细胞和前体细胞的分化是必要的，但它们的作用只是支持它们。在肝细胞生长因子诱导干细胞分化的第一步中，转录因子中的碱性亮氨酸拉链蛋白CCAAT/增强子鸟蛋白（C/EBP）的表达发生了显著变化，当C/EBP的功能在干细胞中受到抑制时，干细胞停止向肝细胞系细胞的转化并活跃地增殖。这些结果首次明确了肝干细胞在肝脏发育中的分化机制。