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Establishment of cell transplantation therapy for Wilson's disease using hepatic stem cells.

建立使用肝干细胞治疗威尔逊氏病的细胞移植疗法。

基本信息

批准号：
13670781
负责人：
TERADA Kunihiko
金额：
$ 2.56万
依托单位：
Akita University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670781/
关键词：
Hepatic stem cell Albumin Collagen Analbuminemic rat Cell transplantation Metabolic liver disease Liver epithelial cell Cell differentiation 肝臓幹細胞 α-フェトプロエインコラーゲンゲルコラーゲンスポンジ肝星細胞

项目摘要

[Aim]In this study, we aimed the establishment of cell transplantation therapy for metabolic liver diseases using hepatic stem cells, previously isolated from a rat liver. To this end, we examined function of the transplanted hepatic stem cells into liver whether cell transplantation was effective to treat metabolic liver diseases including Wilson's disease.[Achievements](1) We have established a liver epithelia cell line, designated hepatic stem like (HSL) cell, from nonparenchymal fraction of healthy rat liver. (2) The HSL cells are small with 20μm in diameter and showed high nucleus/cytoplasm ratios. These cells expressed α-fetoprotein, but not albumin nor cytokeratin 19, indicating the cells have immature phenotype. (3) We cultured the HSL cells in collagen gels cr with hepatic stellate cells to investigate their potential to differentiate. Consequently, both of culture conditions induced the HSL cells to express albumin, showing that the HSL cells are able to differentiate into mature cells. (4) Finally, we examined whether the HSL cells will be able to manifest hepatic function in vivo after transplantation. To this end, we transplanted the HSL cells that were mixed with collagen gel or embedded in collagen sponge into analbuminemic rats. As a result, analbuminemic rats that showed the increased levels of serum albumin were 67% in the rats transplanted the HSL cells with collagen gel and 57% in the rats with collagen sponge. In those rats, the levels of serum albumin increased ten weeks after transplantation and maintained until 25 weeks after transplantation. These results suggest that the HSL cells are potential to differentiate and that the transplanted HSL cells differentiated into albumin producing cells and function as hepatocytes in vivo. The present study implies the possibility of clinical application of HSL cells for metabolic liver diseases.

【目的】利用大鼠肝脏干细胞建立细胞移植治疗代谢性肝病的方法。为此，我们检查了移植到肝脏中的肝干细胞的功能，以确定细胞移植是否能有效治疗包括Wilson病在内的代谢性肝病。【研究成果】（1）从健康大鼠肝脏非实质部分建立了肝上皮细胞系，命名为肝干细胞样（HSL）。(2)HSL细胞体积小，直径约20μm，核质比高。这些细胞表达甲胎蛋白，但不表达白蛋白和细胞角蛋白19，表明细胞具有未成熟表型。(3)我们将HSL细胞与肝星状细胞一起培养在胶原凝胶中以研究其分化潜能。因此，两种培养条件均诱导HSL细胞表达白蛋白，表明HSL细胞能够分化为成熟细胞。(4)最后，我们研究了HSL细胞移植后是否能够在体内表现出肝功能。为此，我们将HSL细胞与胶原凝胶混合或包埋在胶原海绵中移植到无白蛋白血症大鼠体内。结果，在移植了HSL细胞的胶原凝胶组和胶原海绵组中，分别有67%和57%的血清白蛋白水平升高的白蛋白缺乏症大鼠。在这些大鼠中，血清白蛋白水平在移植后10周升高，并维持至移植后25周。这些结果表明，HSL细胞具有分化潜能，并且移植的HSL细胞分化为白蛋白产生细胞，并在体内起肝细胞的作用。本研究为HSL细胞在代谢性肝病的临床应用提供了可能。