门脉高压症患者的脾脏血清通过 IGF-II/ERK 信号通路增强肝干细胞的增殖和自我更新。
Splenic serum from portal hypertensive patients enhances liver stem cell proliferation and self-renewal via the IGF-II/ERK signaling pathway.
机构信息
National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
出版信息
Dig Liver Dis. 2020 Feb;52(2):205-213. doi: 10.1016/j.dld.2019.07.014. Epub 2019 Sep 5.
BACKGROUND
Hypersplenism is a serious complication of portal hypertension (PH) and can affect the prognosis of liver disease. Liver stem cells (LSCs) are involved in liver regeneration and hepatocarcinogenesis after liver cirrhosis.
AIM
To explore the effects and mechanism of the spleen on the proliferation and differentiation of LSCs in PH due to liver cirrhosis.
METHODS
Fetal liver stem cells (FLSCs) were treated with splenic serum from liver cirrhosis patients with hypersplenism and control serum from healthy volunteers, and the proliferation, self-renewal, and IGF-II/ERK signaling pathway of FLSCs were then evaluated.
RESULTS
We found that splenic serum from PH patients promoted FLSC proliferation, colony formation, and Ki-67 expression in vitro. Splenic serum from PH also enhanced FLSC spheroid formation in vitro. Mechanistically, we determined that insulin-like growth factor (IGF)-II concentration was elevated in splenic serum from PH patients and could promote FLSC proliferation and self-renewal. Furthermore, both IGF-II and splenic serum from PH patients enhanced ERK signaling activation through IGF-I receptor (IGF-I R) in FLSCs. Consistently, blocking IGF-I R or ERK signaling could attenuate the effects of splenic serum from PH patients on FLSCs.
CONCLUSIONS
The spleen in PH patients promotes FLSC proliferation and self-renewal through the IGF-II/ERK signaling pathway.
背景
脾功能亢进是门静脉高压（PH）的严重并发症，可影响肝病的预后。肝干细胞（LSCs）参与肝硬化后肝脏再生和肝癌发生。
目的
探讨脾对肝硬化所致 PH 中 LSCs 增殖和分化的影响及其机制。
方法
用肝硬化伴脾功能亢进患者的脾血清和健康志愿者的对照血清处理胎肝干细胞（FLSCs），然后评估 FLSCs 的增殖、自我更新和 IGF-II/ERK 信号通路。
结果
我们发现 PH 患者的脾血清在体外促进 FLSC 的增殖、集落形成和 Ki-67 表达。PH 患者的脾血清还增强了 FLSC 在体外的球体形成。从机制上讲，我们确定 PH 患者的脾血清中胰岛素样生长因子（IGF）-II 浓度升高，并能促进 FLSC 的增殖和自我更新。此外，IGF-II 和 PH 患者的脾血清均可通过 FLSCs 中的 IGF-I 受体（IGF-I R）增强 ERK 信号激活。一致地，阻断 IGF-I R 或 ERK 信号可减弱 PH 患者脾血清对 FLSCs 的作用。
结论
PH 患者的脾脏通过 IGF-II/ERK 信号通路促进 FLSC 的增殖和自我更新。
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