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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.

我们研究了在肝脏再生过程中骨髓细胞是否可以转化为肝构成细胞。将绿色荧光蛋白（GFP）转基因小鼠的BM细胞经全身照射后移植到W/W^v c-kit突变小鼠体内。在得到的W/W^v （BMT-W/W^v）小鼠中，在门静脉周围区观察到GFP阳性细胞。CCl_4或抗fas抗体给予BMT-W/W^v小鼠，GFP阳性细胞沿肝窦发育。这些结果表明肝细胞在肝再生过程中向窦状内皮细胞分化。最近有研究表明，在幼龄大鼠肝脏中可见c-kit受体酪氨酸激酶（KIT）的表达，并在结扎胆总管（BDL）后的胆汁上皮细胞（BEC）中表达上调。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是否会在BDL后的胆汁淤积中增殖。2周龄正常（+/+）大鼠和Ws/Ws大鼠行BDL时，Ws/Ws大鼠肝脏门脉区仅见少量BEC，而+/+大鼠肝脏门脉区可见大量BBC。此外，Ki-67免疫染色显示，2周龄Ws/Ws大鼠的BEC增殖活性远低于同年龄+/+大鼠。相比之下，当6周龄+/+和Ws/Ws大鼠接受BDL时，BEC在+/+和Ws/Ws大鼠的肝脏中增殖相似，并且BEC的增殖活性相当。2周龄大鼠和6周龄大鼠BDL后胆汁淤积反应中BEC增殖的机制可能不同，KIT介导的信号转导在幼龄大鼠未成熟BEC的增殖中起着至关重要的作用。