间质干细胞同种异体移植通过依赖白细胞介素 1 受体拮抗剂的巨噬细胞表型转换减轻肝脏疾病小鼠模型的肝损伤。

Allo-transplantation of mesenchymal stem cells attenuates hepatic injury through IL1Ra dependent macrophage switch in a mouse model of liver disease.

机构信息

Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.

出版信息

J Hepatol. 2015 Dec;63(6):1405-12. doi: 10.1016/j.jhep.2015.07.035. Epub 2015 Aug 11.

DOI:10.1016/j.jhep.2015.07.035

PMID:26276675

Abstract

BACKGROUND & AIMS: Autologous transplantation of mesenchymal stem cells (MSCs) reduces concanavalin A (Con A)-induced hepatic injury in mice. However, the mechanism is unclear and the therapeutic effect of allo-transplantation remains unknown. Our aim was to investigate the effects and mechanisms related to allo-transplantation of MSCs when used to treat Con A hepatic injury.

METHODS

After Con A-induced liver injury was created in C57BL/6J mice, MSCs derived from BALB/c mice or a vehicle control was administered.

RESULTS

Allo-transplantation of MSCs derived from BALB/c mice attenuated hepatic apoptosis in C57BL/6J mice that had undergone Con A-induced liver injury. MSCs increased the level of serum interleukin (IL)-10 and the phosphorylation of hepatic STAT3, but decreased the level of hepatic IFN-γ and phospho-STAT1. Notably, the administered MSCs were trapped mostly in the lungs and promoted the macrophage M2 switch, which contributed to the increased IL10 levels in the lungs and serum. Loss of the therapeutic effect was observed after knock-down of the expression of interleukin 1 receptor antagonist (IL1Ra) in the MSCs. In vitro investigation supported the hypothesis that MSCs are able to switch Con A-stimulated macrophages to the M2 phenotype, which results in an increase in IL10 production.

CONCLUSIONS

Allo-transplantation of MSCs reduces Con A liver injury by increasing IL10 production through an IL1Ra dependent macrophage switch.

摘要

背景与目的

自体间充质干细胞（MSCs）移植可减轻伴刀豆球蛋白 A（Con A）诱导的肝损伤。然而，其机制尚不清楚，同种异体移植的疗效尚不清楚。本研究旨在探讨同种异体 MSC 移植治疗 Con A 肝损伤的作用及相关机制。

方法

在 C57BL/6J 小鼠中建立 Con A 诱导的肝损伤模型后，给予 BALB/c 来源的 MSC 或 vehicle 对照处理。

结果

同种异体移植 BALB/c 来源的 MSC 可减轻 C57BL/6J 小鼠经 Con A 诱导的肝损伤后的肝细胞凋亡。MSC 增加了血清白细胞介素（IL）-10 的水平和肝 STAT3 的磷酸化，但降低了肝 IFN-γ和磷酸化 STAT1 的水平。值得注意的是，给予的 MSC 主要被捕获在肺部，并促进巨噬细胞 M2 转化，这有助于增加肺部和血清中的 IL10 水平。敲低 MSC 中白细胞介素 1 受体拮抗剂（IL1Ra）的表达后，观察到治疗效果丧失。体外研究支持 MSC 能够将 Con A 刺激的巨噬细胞转化为 M2 表型，从而增加 IL10 产生的假说。