Mesenchymal stem cell-secreted prostaglandin E2 ameliorates acute liver failure via attenuation of cell death and regulation of macrophage polarization

Haozhen Ren,Xiaolei Shi,Jinglin Wang,Yang Liu,Haoran Ding

doi:10.1186/s13287-020-02070-2

Haozhen Ren, Xiaolei Shi + Show 3 more

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https://doi.org/10.1186/s13287-020-02070-2

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Abstract

BackgroundAcute liver failure (ALF) is an acute inflammatory liver disease with high mortality. Previous preclinical and clinical trials have confirmed that mesenchymal stem cell (MSC) is a promising therapeutic approach; however, the effect is not satisfied as the underlying molecular mechanisms of MSC in treating ALF remain unclear.MethodsMSC isolated from 4- to 6-week-old C57BL/6 mice were used to treat ALF. Histological and serological parameters were analyzed to evaluate the efficacy of MSC. We explored the molecular mechanism of MSC in the treatment of ALF by detecting liver inflammatory response and hepatocyte death.ResultsIn this study, we found that the therapeutic potential of MSC on ALF is dependent on the secretion of prostaglandin E2 (PGE2), a bioactive lipid. MSC-derived PGE2 inhibited TGF-β-activated kinase 1 (TAK1) signaling and NLRP3 inflammasome activation in liver macrophages to decrease the production of inflammatory cytokines. Meanwhile, macrophages in the liver could be induced to anti-inflammatory (M2) macrophages by MSC-derived PGE2 via STAT6 and mechanistic target of rapamycin (mTOR) signaling, which then promote inflammatory resolution and limit liver injury. Finally, administrating EP4 antagonist significantly ameliorated the therapeutic ability of MSC, which promoted liver inflammation and decreased M2 macrophages.ConclusionsOur results indicate that PGE2 might be a novel important mediator of MSC in treating ALF, which is through inhibiting the liver inflammatory response and hepatocyte death.

Highlights

Acute liver failure (ALF) is a clinical syndrome with high mortality rate, and liver transplantation is the only effective way to cure ALF [1]
mesenchymal stem cell (MSC) protects against ALF via prostaglandin E2 (PGE2) Paralyzed with our previous study [13], MSC protected against ALF through PGE2, as revealed by plasma levels of Alanine aminotransaminase (ALT) and Aspartate aminotransferase (AST) (Fig. 1a) and liver damage in HE staining (Fig. 1b)
MSC ameliorates inflammation in ALF Liver inflammation is associated with hepatocyte damage and death; we examined the inflammatory response in the liver after MSC infusion

Summary

Introduction

Acute liver failure (ALF) is a clinical syndrome with high mortality rate, and liver transplantation is the only effective way to cure ALF [1]. Wang et al Stem Cell Research & Therapy (2021) 12:15 such as tumor necrosis factor (TNF), interleukin (IL)-1β, and reactive oxygen species (ROS) which accelerate liver injury [5]. Most of these inflammatory mediators were secreted by innate immune cells in the liver, including monocytes, macrophages, and dendritic cells (DC), which are activated by damage-associated molecular patterns (DAMPs) released by damaged hepatocytes. Previous preclinical and clinical trials have confirmed that mesenchymal stem cell (MSC) is a promising therapeutic approach; the effect is not satisfied as the underlying molecular mechanisms of MSC in treating ALF remain unclear

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