Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells
Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells
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DOI：
10.1242/dev.00459
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发表时间：
2003-06-01
期刊：
影响因子：
4.6
通讯作者：
Taniguchi, H
中科院分区：
文献类型：
--
作者：
Suzuki, A;Iwama, A;Taniguchi, H
在肝脏发育过程中，许多生长因子(Gf)和细胞外基质(ECM)成分会导致肝实质细胞的分化。由于肝脏含有多种细胞类型，因此很难专门研究它们对肝脏干细胞群的功能影响。对肝脏干细胞的前瞻性分离和克隆检测能够检测GFS和ECM对这一稀有细胞组分的直接影响。使用符合肝脏干细胞标准的先前纯化的细胞，我们研究了GFS和ECM如何调节发育中的肝脏的分化。我们发现，肝细胞生长因子(HGF)诱导白蛋白(ALB)阴性的干细胞早期转化为白蛋白(ALB)阳性的类似肝母细胞的肝前体细胞，然后抑癌素M(OSM)促进其向色氨酸-2，3-双加氧酶(TO)阳性的成熟肝细胞分化。在这一转变过程中，细胞外基质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性的。在HGF诱导干细胞分化的第一步，碱性亮氨酸拉链转录因子CCAAT/增强子结合蛋白(C/EBP)的表达发生了显著变化。当干细胞中的C/EBP功能被抑制时，它们停止分化为肝细胞系细胞，并活跃地增殖。这些发现首次阐明了肝脏干细胞分化在肝脏发育过程中的机制。
In liver development, a number of growth factors (GFs) and components of the extracellular matrix (ECMs) lead to differentiation of liver parenchymal cells. As the liver contains many cell types, specifically investigating their functional effects on hepatic stem cell populations is difficult. Prospective isolation and clonal assays for hepatic stem cells enable the examination of direct effects of GFs and ECMs on this rare cell fraction. Using previously purified cells that fulfill the criteria for hepatic stem cells, we examined how GFs and ECMs regulate differentiation in the developing liver. We show here that hepatocyte growth factor (HGF) induced early transition of albumin (ALB)-negative stem cells to ALB-positive hepatic precursors resembling hepatoblasts and then oncostatin M (OSM) promoted their differentiation to tryptophan-2, 3- dioxygenase (TO)-positive mature hepatocytes. During this transition, ECMs were necessary for the differentiation of stem cells and precursors, but their effects were only supportive. In the first step of stem cell differentiation induced by HGF, the expression of CCAAT/enhancer binding protein (C/EBP), a basic leucine zipper transcription factor, changed dramatically. When C/EBP function was inhibited in stem cells, they stopped differentiating to hepatocyte-lineage cells and proliferated actively. These are the first findings to illustrate the mechanism of hepatic stem cell differentiation in liver development.