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

Abstract

Background Acute 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. Methods MSC 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. Results In 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. Conclusions Our 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.

Heat shock preconditioning mesenchymal stem cells attenuate acute lung injury via reducing NLRP3 inflammasome activation in macrophages

“…Interestingly, we also observed, for the first time, that HS pretreatment not only promoted the effects of MSCs in lung protection but also enhanced the potential of MSCs to modulate the NLRP3 inflammasome in macrophages. Wang et al proved that 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 [ 55 ]. Therefore, in this study, we measured the levels of cytokines secreted by MSCs to determine how HS pretreatment enhanced the therapeutic potential of MSCs.…”

Mesenchymal Stem Cell-Macrophage Crosstalk and Maintenance of Inflammatory Microenvironment Homeostasis

“…Nakajima and HongLong Zhou reported that MSCs can effectively improve spinal cord injury by polarizing macrophages from the M1 to M2 type (Nakajima et al, 2012;Zhou et al, 2016). Other studies have also reported that MSCs can alleviate liver diseases, such as acute liver injury and liver fibrosis, by inhibiting proinflammatory M1 cells and inducing M2 anti-inflammatory cells (Li C. et al, 2019;Wang et al, 2021). Reports also show that MSCs can improve diabetes by inducing macrophage polarization (Yin et al, 2018;Gao et al, 2019).…”

“…This therapeutic potency was possibly mediated by MSC production of PGE2 to polarize M2 macrophages (Cao et al, 2020). Wang et al (2021) reported that MSCs can protect against D-galactosamine (D-Gal)-induced liver failure, and they found that MSCs regulate macrophage polarization by secreting PGE2. In addition, studies have reported that MSCs improve cardiac injury by increasing M2 macrophages through the COX-2-PGE2 pathway (Jin et al, 2019(Jin et al, , 2020.…”

“…Previous studies indicated that IL-1β derived from macrophages may stimulate MSCs to secrete IL-1RA and PGE2, which leads to the polarization of Ohara et al, 2018;Kojima et al, 2019;Luo et al, 2019;Song et al, 2020 Ischemia/Reperfusion (IR)-induced sterile inflammatory liver injury MSC reprogram macrophage toward anti-inflammatory M2 phenotype Reduced hepatocellular damage; Diminished liver inflammation Li C. et al, 2019;Sheng et al, 2021 Acute liver failure MSC induced anti-inflammatory (M2) macrophages; reduced levels of macrophage Ameliorated hepatocyte death and liver inflammatory response. Li et al, 2017Li et al, , 2021Liu et al, 2018;Hwang et al, 2019;Liang et al, 2019;Shao et al, 2020;Wang et al, 2021 Ben-Mordechai et al, 2013;Xu et al, 2019;Gao et al, 2020;Liao et al, 2020 Atherosclerosis Stimulate the production of anti-inflammatory factor IL-10, and reduce the production of TNF-α by macrophage.…”

Modulation of Prostanoids Profile and Counter-Regulation of SDF-1α/CXCR4 and VIP/VPAC2 Expression by Sitagliptin in Non-Diabetic Rat Model of Hepatic Ischemia-Reperfusion Injury

“…Consistently, inhibition of upstream PLA2 by dexamethasone [ 7 , 8 ] or downstream inducible PGE 2 synthase (mPGES-1) [ 9 ] confers protection as well. On the other, mesenchymal stem cell-derived PGE 2 [ 10 ] or PGE 2 signaling via EP 4 receptor [ 11 ] are claimed to exert hepatoprotective effects during liver injury.…”