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Regenerative medicine for liver diseases : Analysis of the development and differentiation of hepatic oval cells

肝病再生医学：肝卵圆细胞的发育和分化分析

基本信息

批准号：
15590356
负责人：
TSUJIMURA Tohru
金额：
$ 2.3万
依托单位：
Hyogo College of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

We first examined the expression of Oncostatin M(OSM) and OSM-specific receptor(OSM-R) in the liver undergoing regeneration in the 2-acetylaminofluorene/partial hepatectomy(AAF/PH) model. OSM was expressed in both oval cells and Kupffer cells, but OSM-R was exclusively expressed in oval cells. When rat oval cells (OC15-5) were incubated in the conditioned medium of 293T cells expressing rat OSM cDNA, this resulted in suppression of growth, changes in morphology to possess microvilli and large cytoplasm with developed organells, and expression of hepatocyte markers, such as tyrosine amino transferase and tryptophan oxygenase, in OC15-5 cells. These results indicate that OSM is a key mediator for induction of the differentiation of OC15-5 cells into hepatocytes, and suggest that the OSM/OSM-R system plays a pivotal role in the differentiation of oval cells into hepatocytes, thereby promoting liver regeneration.Next, we examined the expression of Dlk in the AAF/PH model. Immunofluoresence staining analysis revealed that Dlk+ cells expressed oval cell markers, cytokeratin 19(CK19) and α-fetoprotein, indicating that Dlk is expressed in oval cells. However, Dl1k+ cells accounted for only about 20% of total CK19+ oval cells. Dlk+ cells were localized more distantly from the portal vein than Dlk- cells, and were adjacent to mature hepatocytes. Furthermore, at day 12 after PH, only 3% of Dlk+ oval cells expressed Ki67, whereas about 13% of total oval cells expressed Ki67, indicating that Dlk+ oval cells are less proliferative than Dlk- oval cells. Taken together, these results demonstrate that Dlk is expressed in a subpopulation of oval cells and that Dlk+ cells represent intermediate cells between Dlk- oval cells and mature hepatocytes.

我们首先在2-乙酰氨基芴/部分肝切除术（AAF/PH）模型中检测了肿瘤抑制素M（OSM）和OSM特异性受体（OSM- r）在肝脏再生中的表达。OSM在卵圆细胞和Kupffer细胞中均有表达，但OSM- r仅在卵圆细胞中表达。将大鼠卵圆细胞（OC15-5）置于表达大鼠OSM cDNA的293T细胞的条件培养基中孵育，OC15-5细胞生长受到抑制，细胞形态发生变化，具有微绒毛和大细胞质，细胞器发育，并表达肝细胞标志物，如酪氨酸氨基转移酶和色氨酸加氧酶。这些结果表明OSM是诱导OC15-5细胞向肝细胞分化的关键介质，并提示OSM/OSM- r系统在卵形细胞向肝细胞分化从而促进肝脏再生中起关键作用。接下来，我们检测了Dlk在AAF/PH模型中的表达。免疫荧光分析显示，Dlk+细胞表达卵形细胞标记物、细胞角蛋白19（CK19）和α-胎蛋白，表明Dlk在卵形细胞中表达。而Dl1k+细胞仅占CK19+卵圆细胞总数的20%左右。与Dlk-细胞相比，Dlk+细胞定位于离门静脉较远的地方，并与成熟肝细胞相邻。此外，在PH后第12天，只有3%的Dlk+卵形细胞表达Ki67，而约13%的卵形细胞表达Ki67，表明Dlk+卵形细胞的增殖能力低于Dlk-卵形细胞。综上所述，这些结果表明Dlk在卵形细胞亚群中表达，而Dlk+细胞代表介于Dlk-卵形细胞和成熟肝细胞之间的中间细胞。

项目成果

期刊论文数量（37）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tanimizu N et al.: "Isolation of hepatoblasts based on the expression of Dlk/Pref-1"J Cell Sci. 116. 1775-1786 (2003)

Tanimizu N 等人：“基于 Dlk/Pref-1 表达的肝母细胞的分离”J Cell Sci。

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

The origin of biliary ductular cells that appear in the spleen after transplantation of hepatocytes

DOI：
10.3727/000000004772664860
发表时间：
2004-01-01
期刊：
CELL TRANSPLANTATION
影响因子：
3.3
作者：
Fukuda, K;Sugihara, A;Terada, N
通讯作者：
Terada, N

Oncostatin M inhibits proliferation of rat oval cells, OC15-5, inducing differentiation into hepatocytes.

DOI：
10.1016/s0002-9440(10)62292-4
发表时间：
2005-03
期刊：
The American journal of pathology
影响因子：
0
作者：
A. Okaya;J. Kitanaka;N. Kitanaka;M. Satake;Yuna Kim;K. Terada;T. Sugiyama;M. Takemura;J. Fujimoto;N. Terada;A. Miyajima;T. Tsujimura
通讯作者：
A. Okaya;J. Kitanaka;N. Kitanaka;M. Satake;Yuna Kim;K. Terada;T. Sugiyama;M. Takemura;J. Fujimoto;N. Terada;A. Miyajima;T. Tsujimura

Satake M et al.: "Role of c-kit receptor tyrosine kinase-mediated signal transduction in proliferation of bile epithelial cells in young rats after ligation of bile duct : A study using Ws/Ws c-kit mutant rats"J Hepatol. 39. 86-92 (2003)

Satake M 等人：“c-kit 受体酪氨酸激酶介导的信号转导对年轻大鼠胆管结扎后胆汁上皮细胞增殖的作用：使用 Ws/Ws c-kit 突变大鼠的研究”J Hepatol。