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Studies of regenerative medicine on differentiation into hepatic and bile duct cells for preclinical trial to surgery

再生医学研究分化为肝和胆管细胞的临床前试验和手术

基本信息

批准号：
18390343
负责人：
TERAOKA Hirobumi
金额：
$ 11.13万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Although the intrahepatic bile duct has been suggested to be a source of hepatic progenitor cells in the severely damaged liver, little attention has been paid to the question of whether hepatic progenitor cells exist in the extrahepatic bile duct (EHBD). We examined the phenotypic changes of the mouse EHBD following the bile duct ligation. After bile duct ligation, the number of c-kit-positive epithelilal cells increased in the EHBD. The ligated EHBD expressed mRNA for hepatic progenitor cell markers. Hepatocyte markers were also transiently detected in the EHBD and gall bladder after a bile duct ligation. Hepatic progenitor cells positive for both c-kit and albumin were found in the cultured EHBD population. These results suggest a potential of the EHBD and gall bladder as useful transplantable sources for liver injury.Avoiding the limitations of the adult liver niche, transplantation of hepatic stem/progenitor cells into fetal liver is desirable to analyze immature cells in a hepati … More c developmental environment. Here, we established a new monitor tool for cell fate of hepatic progenitor cells transplanted into the mouse fetal liver by using ex utero surgery. When embryonic day (ED) 14.5 hepatoblasts were injected into the ED14.5 fetal liver, the transplanted cells expressed albumin abundantly or α-fetoprotein weakly, and contained glycogen in the neonatal liver, indicating that transplanted hepatoblasts can proliferate and differentiate in concord with surrounding recipient parenchymal cells. The transplanted cells became mature in the liver of 6-week-old mice. Furthermore, this method was applicable to transplantation of hepatoblast-like cells derived from mouse ES cells. These data indicate that this unique technique will provide a new in vivo experimental system for studying cell fate of hepatic stem/progenitor cells and liver organogenesis.We revealed involvement of VEGF in efficient differentiation into hepatocyte-like cells, biological function of the undifferentiated cell marker gene DPPA4, and epigenetic regulation of the mature hepatocyte marker gene MAT1A. Less

尽管肝内胆管被认为是严重受损肝脏中肝祖细胞的来源，但很少有人关注肝外胆管（EHBD）中是否存在肝祖细胞的问题。我们检查了胆管结扎后小鼠 EHBD 的表型变化。胆管结扎后，EHBD 中 c-kit 阳性上皮细胞的数量增加。连接的 EHBD 表达肝祖细胞标记物的 mRNA。胆管结扎后，EHBD 和胆囊中也短暂检测到肝细胞标记物。在培养的 EHBD 群体中发现 c-kit 和白蛋白均呈阳性的肝祖细胞。这些结果表明 EHBD 和胆囊有可能成为治疗肝损伤的有用移植来源。为了避免成人肝脏生态位的限制，将肝干/祖细胞移植到胎儿肝脏中对于分析肝脏发育环境中的未成熟细胞是可取的。在这里，我们建立了一种新的监测工具，用于通过宫外手术移植到小鼠胎儿肝脏中的肝祖细胞的细胞命运。当胚胎日（ED）14.5的成肝细胞被注射到ED14.5的胎儿肝脏中时，移植的细胞大量表达白蛋白或弱表达甲胎蛋白，并且在新生儿肝脏中含有糖原，这表明移植的成肝细胞可以与周围的受体实质细胞一致地增殖和分化。移植的细胞在六周大小鼠的肝脏中成熟。此外，该方法适用于小鼠ES细胞来源的成肝细胞样细胞的移植。这些数据表明，这种独特的技术将为研究肝干/祖细胞的细胞命运和肝器官发生提供新的体内实验系统。我们揭示了VEGF参与肝细胞样细胞的高效分化、未分化细胞标记基因DPPA4的生物学功能以及成熟肝细胞标记基因MAT1A的表观遗传调控。较少的