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Establishment of new therapeutic modality for liver failure using hepatic stem cells (Remodeling of the injured liver of toxin receptor-mediated cell knockout (TRECK) mice)

利用肝干细胞建立肝衰竭新治疗方式（毒素受体介导细胞敲除（TRECK）小鼠受损肝脏的重塑）

基本信息

批准号：
16390361
负责人：
IKAI Iwao
金额：
$ 9.22万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390361/
关键词：
Hepatic stem cells ES cells Cell transplantation therapy TRECK mouse

项目摘要

The aim of this research is establishment of new therapeutic modality for liver failure using hepatic stem cells. We have already reported as follows: 1) Enrichment of hepatic stem cells from mouse fetal and adult liver. 2) Thyl positive mesenchymal cells derived from mouse fetal liver promoted the in vitro maturation of hepatic stem cells into hepatocytes. Applying these findings, we have successfully produced hepatocytes differentiation from mouse embryonic stem cells. In this research, we applied "toxin receptor-mediated cell knockout (TRECK)" technique to produce alb-DTR transgenic mice, which expressed diphtheria toxin receptor (DTR) specifically on the surface of hepatocytes. We produced homozygous alb-DTR transgenic mice to induce dose-dependent and reproducible liver injury by diphtheria toxin administration. This is ideal model for investigation of functional remodeling of transplanted cells in the lethally injured liver similar to fulminant hepatitis. After the transplantatio … More n of 1×10^6 cells/body of hepatic stem/progenitor cells derived from E13.5 fetal liver of Green Fluorescent Protein (GFP)-transgenic mice into the liver of homozygous alb-DTR transgenic mice, we identified continuous growth and albumin production of transplanted cells in vivo. Furthermore, mortality of acute liver injury of transplanted group was statistically improved compared to that of non-transplanted group. In addition, we are now identifying the same results as improvement of mortality of alb-DTR mice by cell transplantation of hepatic stem/progenitor cells derived from mouse embryonic stem cells. On the other hand, morphologically identified two types of cells consisting of Thyl-positive mesenchymal cells derived from fetal liver were discriminated by the expression of glycoprotein 38 (gp38). Gp38-positive cells promoted in vitro maturation of hepatic stem/progenitor cells via cell-to-cell contact, wheras gp38-negative cells maintained undifferentiated state of hepatic stem/progenitor cells. We are now on the course of further investigation of gp38-positive and negative mesenchymal cells. Less

本研究的目的是建立肝干细胞治疗肝衰竭的新模式。我们已经报道了以下内容：1）从小鼠胎肝和成体肝中富集肝干细胞。2)小鼠胎肝Thyl阳性间充质细胞促进肝干细胞体外成熟为肝细胞。应用这些发现，我们已经成功地从小鼠胚胎干细胞分化为肝细胞。本研究应用“毒素受体介导的细胞敲除（TRECK）”技术制备了白喉毒素受体（DTR）特异性表达于肝细胞表面的alb-DTR转基因小鼠。我们生产了纯合子alb-DTR转基因小鼠，通过白喉毒素给药诱导剂量依赖性和可重复的肝损伤。这是研究移植细胞在类似于暴发性肝炎的致死性损伤肝脏中的功能重建的理想模型。移植后. ...更多信息将来自绿色荧光蛋白（GFP）转基因小鼠E13.5胎肝的肝干/祖细胞以1×10^6个细胞/体的量移植到纯合子alb-DTR转基因小鼠的肝脏中，我们鉴定了移植细胞在体内的连续生长和白蛋白产生。此外，移植组急性肝损伤死亡率较非移植组有统计学改善。此外，我们现在正在鉴定与通过细胞移植源自小鼠胚胎干细胞的肝干/祖细胞来改善alb-DTR小鼠的死亡率相同的结果。另一方面，通过糖蛋白38（gp 38）的表达来区分形态学鉴定的由来自胎肝的Thyl阳性间充质细胞组成的两种类型的细胞。gp 38阳性细胞通过细胞间接触促进肝干/祖细胞的体外成熟，而gp 38阴性细胞维持肝干/祖细胞的未分化状态。我们现在正在进一步研究gp 38阳性和阴性间充质细胞。少