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Analysis of liver regeneration : A study using c-kit mutants

肝再生分析：使用 c-kit 突变体的研究

基本信息

批准号：
13670232
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：
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-13670232/
关键词：
c-kit receptor tyrosine kinase transplantation W W^v mice sinusoid endothelial cells liver regeneration Ws Ws rats liver development bile epithelial cells

项目摘要

We examined whether bone marrow (BM) cells can commit to liver-consisting cells during liver regeneration. BM cells of green fluorescent protein (GFP) transgenic mice were transplanted into W/W^v c-kit mutant mice after whole-body irradiation. In the resulting W/W^v (BMT-W/W^v) mice, GFP positive cells were observed at the periportal region. When CCl_4 or anti-Fas antibody was administered to BMT-W/W^v mice, GFP positive cells developed along liver sinusoid. These results suggest that BM cells differentiate to sinusoid endothelial cells during liver regeneration.Recently, it has been shown that the expression of c-kit receptor tyrosine kinase (KIT) is seen in the liver of young rats, and its expression is up-regulated in bile epithelial cells (BEC) after ligation of the common bile duct (BDL). To clarify a role of KIT in BEC, we examined whether BEC of Ws/Ws c-kit mutant rats could proliferate in response to bile stasis after BDL. When 2-week-old normal (+/+) and Ws/Ws rats underwent BDL, only a few BEC were found in the portal field of livers of Ws/Ws rats, whereas many BBC were found in that of +/+ rats. Furthermore, Ki-67 immunostaining showed that the proliferative activity of BEC in 2-week-old Ws/Ws rats was much lower than that of +/+ rats of the same age. In contrast, when 6-week-old +/+ and Ws/Ws rats underwent BDL, BEC similarly proliferated in the livers of +/+ and Ws/Ws rats, and the proliferative activity of BEC was comparable. It is likely that the mechanism whereby BEC proliferate in response to bile stasis after BDL is different between 2-week-old and 6-week-old rats, and KIT mediated-signal transduction plays a crucial role in the proliferation of immature BEC in young rats.

我们研究了骨髓(BM)细胞在肝脏再生过程中是否能转化为肝脏细胞。将绿色荧光蛋白(GFP)转基因小鼠的骨髓细胞经全身照射后移植到W/W、v、c-kit突变小鼠体内。在W/W^v(BMT-W/W^v)小鼠中，在汇管区周围可见GFP阳性细胞。给BMT-W/W^v小鼠注射CCl_4或抗Fas抗体后，GFP阳性细胞沿肝窦发育。这些结果表明，BM细胞在肝再生过程中分化为肝窦状内皮细胞。最近有研究表明，c-kit受体酪氨酸激酶(KIT)在幼年大鼠肝脏中表达，结扎胆总管(BDL)后，其在胆汁上皮细胞(BEC)中的表达上调。为了阐明KIT在BEC中的作用，我们检测了Ws/Ws c-kit突变大鼠的BEC在胆汁淤积后是否能够增殖。2周龄正常(+/+)和Ws/Ws大鼠BDL后，Ws/Ws大鼠肝门管区仅见少量BEC，而+/+大鼠则可见大量BBC。此外，Ki-67免疫组织化学染色显示2周龄Ws/Ws大鼠的BEC增殖活性明显低于同龄+/+大鼠。相比之下，6周龄+/+和Ws/Ws大鼠进行BDL时，BEC在+/+和Ws/Ws大鼠肝脏中的增殖情况相似，BEC的增殖活性相似。2周龄和6周龄BDL后BEC增殖反应胆汁淤积的机制可能不同，KIT介导的信号转导在幼年大鼠BEC增殖中起关键作用。