MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation

Primary sclerosing cholangitis(PSC)is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis,with no curative treatment available,and liver transplantation is inevitable for end-stage patients.Human placentalmesenchymal stem cell(hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis,inhibit collagen production and possess immunomodulatory properties in autoimmune liver disease.Here,we prepared hpMSC-derived exosomes(Exo^(MSC))and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2^(−/−)mice and multicellular organoids established from PSC patients.The results showed that Exo^(MSC) ameliorated liver fibrosis in Mdr2^(−/−)mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis,and the percentage of CD4+IL-17A+T cells was reduced both in Exo^(MSC)-treated Mdr2^(−/−)mice(Mdr2^(−/−)-Exo)in vivo and Exo^(MSC)-treated Th17 differentiation progressed in vitro.Furthermore,Exo^(MSC) improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular organoids.Thus,our data demonstrate the antifibrosis effect of Exo^(MSC) in PSC disease by inhibiting Th17 differentiation,and ameliorating the Th17-induced microenvironment,indicating the promising potential therapeutic role of Exo^(MSC) in liver fibrosis of PSC or Th17-related diseases.

Human Placental Mesenchymal Stem Cells Relieve Primary Sclerosing Cholangitis via Upregulation of TGR5 in Mdr2^(-/-)Mice and Human Intrahepatic Cholangiocyte Organoid Models

Primary sclerosing cholangitis(PSC)is a biliary disease accompanied by chronic inflammation of the liver and biliary stricture.Mesenchymal stem cells(MSCs)are used to treat liver diseases because of their immune regulation and regeneration-promoting functions.This study was performed to explore the therapeutic potential of human placental MSCs(hP-MSCs)in PSC through the Takeda G protein-coupled receptor 5(TGR5)receptor pathway.Liver tissues were collected from patients with PSC and healthy donors(n=4)for RNA sequencing and intrahepatic cholangiocyte organoid construction.hP-MSCs were injected via the tail vein into Mdr2^(-/-),bile duct ligation(BDL),and 3,5-diethoxycarbonyl-1,4-dihydrocollidine(DDC)mouse models or co-cultured with organoids to confirm their therapeutic effect on biliary cholangitis.Changes in bile acid metabolic profile were analyzed by liquid chromatography/tandem mass spectrometry(LC-MS/MS).Compared with healthy controls,liver tissues and intrahepatic cholangiocyte organoids from PSC patients were characterized by inflammation and cholestasis,and marked downregulation of bile acid receptor TGR5 expression.hP-MSC treatment apparently reduced the inflammation,cholestasis,and fibrosis in Mdr2^(-/-),BDL,and DDC model mice.By activating the phosphatidylinositol 3 kinase/extracellular signal-regulated protein kinase pathway,hP-MSC treatment promoted the proliferation of cholangiocytes,and affected the transcription of downstream nuclear factorκB through regulation of the binding of TGR5 and Pellino3,thereby affecting the cholangiocyte inflammatory phenotype.

Prognostic Nomogram for Patients with Hepatitis E Virus-related Acute Liver Failure:A Multicenter Study in China

Background and Aims:Timely and effective assessment scoring systems for predicting the mortality of patients with hepatitis E virus-related acute liver failure(HEV-ALF)are urgently needed.The present study aimed to establish an effective nomogram for predicting the mortality of HEV-ALF patients.Methods:The nomogram was based on a cross-sectional set of 404 HEV-ALF patients who were identified and enrolled from a cohort of 650 patients with liver failure.To compare the performance with that of the model for end-stage liver disease(MELD)scoring and CLIF-Consortiumacute-on-chronic liver failure score(CLIF-C-ACLFs)models,we assessed the predictive accuracy of the nomogram using the concordance index(C-index),and its discriminative ability using time-dependent receiver operating characteristics(td-ROC)analysis,respectively.Results:Multivariate logistic regression analysis of the development set carried out to predict mortality revealed that γ-glutamyl transpeptidase,albumin,total bilirubin,urea nitrogen,creatinine,international normalized ratio,and neutrophil-to-lymphocyte ratio were independent factors,all of which were incorporated into the new nomogram to predict the mortality of HEV-ALF patients.The area under the curve of this nomogram for mortality prediction was 0.671(95%confidence interval:0.602-0.740),which was higher than that of the MELD and CLIF-C-ACLFs models.Moreover,the td-ROC and decision curves analysis showed that both discriminative ability and threshold probabilities of the nomogram were superior to those of the MELD and CLIF-C-ACLFs models.A similar trend was observed in the validation set.Conclusions:The novel nomogram is an accurate and efficient mortality prediction method for HEV-ALF patients.

Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1αpathways

Accumulating evidence has confirmed the links between transfer RNA(tRNA)modifications and tumor progression.The present study is the first to explore the role of tRNA methyltransferase 5(TRMT5),which catalyzes the m1G37 modification of mitochondrial tRNAs in hepatocellular carcinoma(HCC)progression.Here,based on bioinformatics and clinical analyses,we identified that TRMT5 expression was upregulated in HCC,which correlated with poor prognosis.Silencing TRMT5 attenuated HCC proliferation and metastasis both in vivo and in vitro,which may be partially explained by declined extracellular acidification rate(ECAR)and oxygen consumption rate(OCR).Mechanistically,we discovered that knockdown of TRMT5 inactivated the hypoxia-inducible factor-1(HIF-1)signaling pathway by preventing HIF-1αstability through the enhancement of cellular oxygen content.Moreover,our data indicated that inhibition of TRMT5 sensitized HCC to doxorubicin by adjusting HIF-1α.In conclusion,our study revealed that targeting TRMT5 could inhibit HCC progression and increase the susceptibility of tumor cells to chemotherapy drugs.Thus,TRMT5 might be a carcinogenesis candidate gene that could serve as a potential target for HCC therapy.