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lderitification and analysis of the factors related to the proliferation and differentiation of the adult liver progeritor cells

成体肝祖细胞增殖分化相关因素的解析及分析

基本信息

批准号：
17390362
负责人：
MIWA Shiro
金额：
$ 10.19万
依托单位：
Shinshu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

Infra present study, we analyzed the factors related to the proliferation and differentiation of the Inter progenitor cells.We obtained the following new findings.1) Ductular reaction (DR) in the liver are thought to be result from progenitor cell proliferation. We analyzed the DR in submassive hepatic necrosis (SHN) in human livers. Cells in DR expressed high level of c-met, NCAM, β-1, α 6 integrin, These cells also specifically expressed CD133 and DLK. DR always resided in a laminin rich matrix and closely contacted with o SMA positive cells. The area in which the cell differentiated toward hepatocytes contained high level of TGF a and TGF β 1 and the cell differentiated toward hepatocytes strongly expressed these receptors. These results indicated microenvironment determine the fate of progenitor cell differentiation.2) The roles of bone marrow cells (BMCs) in hepatic regeneration and carcinogenesis are still unknown. We analyzed whether oval cells are derived from BMCs and whether preneoplastic nodules or HCCs originate from BMCs in the choline-deficient, ethionine-supplemented (CDE) diet rat model. To clarify the origin of constituent cells in the liver, we transplanted BMCs from green fluorescent protein (GFP)-transgenic female rats into male rats, which were then exposed to a CDE diet to induce hepatocarcinogenesis. Some oval cells showed both donor-derived GFP expression and the recipient-specific Y chromosome, indicating that donor BMCs fused with recipient oval cells. Several preneoplastic nodules (precancerous lesions) were induced by CDE treatment. However, these preneoplastic nodules were not GFP-positive. In conclusion, this study has produced two major findings. First, BMCs fuse with some oval cells. Second, BMC-fused oval cells and BMCs might not have malignant potential in the CDE-treated rat model.

本研究通过对肝内祖细胞增殖分化相关因素的分析，获得以下新的发现：1）肝内小管反应（Ductular reaction，DR）被认为是肝内祖细胞增殖的结果。我们分析了人类肝脏亚大块肝坏死（SHN）的DR。DR中的细胞表达高水平的c-met、NCAM、β-1、α 6整合素，这些细胞还特异性表达CD 133和DLK。DR常位于富含层粘连蛋白的基质中，与SMA阳性细胞紧密接触.向肝细胞分化的细胞的区域含有高水平的TGF α和TGF β 1，并且向肝细胞分化的细胞强烈表达这些受体。这些结果表明微环境决定了祖细胞分化的命运。2）骨髓细胞（BMCs）在肝再生和癌变中的作用尚不清楚。我们分析了卵圆细胞是否来源于BMCs，以及肿瘤前结节或HCC是否来源于胆碱缺乏，乙硫氨酸补充（CDE）饮食大鼠模型中的BMCs。为了阐明肝脏中组成细胞的起源，我们将绿色荧光蛋白（GFP）转基因雌性大鼠的BMCs移植到雄性大鼠中，然后将其暴露于CDE饮食以诱导肝癌发生。一些卵圆细胞显示出供体来源的GFP表达和受体特异性Y染色体，表明供体BMCs与受体卵圆细胞融合。CDE治疗诱导了几个癌前结节（癌前病变）。然而，这些癌前结节不呈GFP阳性。总之，这项研究产生了两个主要发现。首先，BMC与一些卵圆细胞融合。第二，骨髓基质细胞融合卵圆细胞和骨髓基质细胞可能没有恶性潜能的CDE治疗的大鼠模型。