Liver fibrosis is a significant health burden,marked by the consistent deposition of collagen.Unfortunately,the currently available treatment approaches for this condition are far from optimal.Lysyl oxidase-like prote...Liver fibrosis is a significant health burden,marked by the consistent deposition of collagen.Unfortunately,the currently available treatment approaches for this condition are far from optimal.Lysyl oxidase-like protein 2(LOXL2)secreted by hepatic stellate cells(HSCs)is a crucial player in the cross-linking of matrix collagen and is a significant target for treating liver fibrosis.Mesenchymal stem cell-derived small extracellular vesicles(MSC-sEVs)have been proposed as a potential treatment option for chronic liver disorders.Previous studies have found that MSC-sEV can be used for microRNA delivery into target cells or tissues.It is currently unclear whether microRNA-4465(miR-4465)can target LOXL2 and inhibit HSC activation.Additionally,it is uncertain whether MSC-sEV can be utilized as a gene therapy vector to carry miR-4465 and effectively inhibit the progression of liver fibrosis.This study explored the effect of miR-4465-modified MSC-sEV(MSC-sEVmiR-4465)on LOXL2 expression and liver fibrosis development.The results showed that miR-4465 can bind specifically to the promoter of the LOXL2 gene in HSC.Moreover,MSC-sEVmiR-4465 inhibited HSC activation and collagen expression by downregulating LOXL2 expression in vitro.MSC-sEVmiR-4465 injection could reduce HSC activation and collagen deposition in the CCl4-induced mouse model.MSC-sEVmiR-4465 mediating via LOXL2 also hindered the migration and invasion of HepG2 cells.In conclusion,we found that MSC-sEV can deliver miR-4465 into HSC to alleviate liver fibrosis via altering LOXL2,which might provide a promising therapeutic strategy for liver diseases.展开更多
Alcoholic liver disease(ALD)represents a wide spectrum of disease from simple steatosis to cirrhosis.Although there have been multiple attempts to treat ALD,its treatment is still based on abstinence from alcohol and ...Alcoholic liver disease(ALD)represents a wide spectrum of disease from simple steatosis to cirrhosis.Although there have been multiple attempts to treat ALD,its treatment is still based on abstinence from alcohol and using corticosteroids in specified cases.However,nearly 40%of patients with ALD who are in need of treatment are unresponsive to the current treatments,which implies a new paradigm shift for the treatment of ALD.Traditionally,earlier studies have focused on the abnormal metabolism occurring in the hepatocytes as a protagonist in the pathogenesis of ALD.However,increasing evidence suggests that non-parenchymal cells,such as hepatic stellate cells(HSCs),Kupffer cells,liver sinusoidal endothelial cells,and immune cells around the hepatocytes have critical roles in multiple stages of ALD either by direct or indirect cell-to-cell interactions.For instance,in the early stage of ALD,Kupffer cells and HSCs located closely to hepatocytes contribute to the development of alcoholic steatosis and inflammation through the secretion of various inflammatory cytokines(immunologic pathways)and the activation of the endocannabinoid system(metabolic pathways).While the stage of ALD progresses to alcoholic hepatitis and fibrosis,various cell-to-cell interactions with infiltrating immune cells become highly significant at the multicellular level.This review explains the diverse roles of non-parenchymal cells in the progression of ALD,as well as potential therapeutic strategies to treat ALD.展开更多
An effective therapeutic regimen for hepatic fibrosis requires a deep understanding of the pathogenesis mechanism.Hepatic fibrosis is characterized by activated hepatic stellate cells(aHSCs)with an excessive productio...An effective therapeutic regimen for hepatic fibrosis requires a deep understanding of the pathogenesis mechanism.Hepatic fibrosis is characterized by activated hepatic stellate cells(aHSCs)with an excessive production of extracellular matrix.Although promoted activation of HSCs by M2 macrophages has been demonstrated,the molecular mechanism involved remains ambiguous.Herein,we propose that the vitamin D receptor(VDR)involved in macrophage polarization may regulate the communication between macrophages and HSCs by changing the functions of exosomes.We confirm that activating the VDR can inhibit the effect of M2 macrophages on HSC activation.The exosomes derived from M2 macrophages can promote HSC activation,while stimulating VDR alters the protein profiles and reverses their roles in M2 macrophage exosomes.Smooth muscle cell-associated protein 5(SMAP-5)was found to be the key effector protein in promoting HSC activation by regulating autophagy flux.Building on these results,we show that a combined treatment of a VDR agonist and a macrophage-targeted exosomal secretion inhibitor achieves an excellent anti-hepatic fibrosis effect.In this study,we aim to elucidate the association between VDR and macrophages in HSC activation.The results contribute to our understanding of the pathogenesis mechanism of hepatic fibrosis,and provide potential therapeutic targets for its treatment.展开更多
Background:Biliary atresia is a rare congenital bile duct disease that is the leading cause of liver fibrosis in neonates.Granulocyte colony-stimulating factor(GCSF)is a potential therapy for hepatocellular diseases,b...Background:Biliary atresia is a rare congenital bile duct disease that is the leading cause of liver fibrosis in neonates.Granulocyte colony-stimulating factor(GCSF)is a potential therapy for hepatocellular diseases,but data on GCSF for cholestatic conditions remain limited.Materials and methods:The current study examines the role of GCSF in improving bile duct obstruction in mice.Two doses were administered:10.0 mg/kg/day and 61.5 mg/kg/day,which is the animal equivalent dose of 5.0 mg/kg in humans.Seven days(D7)after bile duct ligation(BDL),Swiss mice were treated with phosphate buffered saline or GCSF for 5 days.The intrahepatic adaptive response of BDL mice was evaluated on postsurgical days D12,D19,and D26.Results:Treatment with 61.5 mg/kg of GCSF resulted in a significant increase in circulating leukocytes and neutrophils on D12.Amelioration of liver injury,as shown by reduced aspartate aminotransferase levels,increased albumin levels and survival rate,as well as reduced intrahepatic inflammation and hepatic myeloperoxidase expression,downregulated ductular proliferation,periportal fibroblast activation,and fibrosis,enhanced expressions of hepatocyte growth factor,peroxisome proliferator-activated receptoralpha,and ki67,and suppressed expression of cleaved caspase-3 protein,was noted after treatment with 61.5 mg/kg of GCSF.Additionally,GCSF treatment was associated with an increased number of intrahepatic cd3-Sca1tc-Kitt bone marrow cells.展开更多
基金supported by the National Natural Science Foundation of China(No.82272421)the Jiangsu Provincial Key Research and Development Program(No.BE2021690)+2 种基金the Changzhou's 14th Five-year Plan Project to Train Highlevel Health Professionals(No.2022CZLJ027)the Scientific Project of Jiangsu Health Commission(No.Z2020038)the Changzhou Sci&Tech Program(No.CJ20220164),China.
文摘Liver fibrosis is a significant health burden,marked by the consistent deposition of collagen.Unfortunately,the currently available treatment approaches for this condition are far from optimal.Lysyl oxidase-like protein 2(LOXL2)secreted by hepatic stellate cells(HSCs)is a crucial player in the cross-linking of matrix collagen and is a significant target for treating liver fibrosis.Mesenchymal stem cell-derived small extracellular vesicles(MSC-sEVs)have been proposed as a potential treatment option for chronic liver disorders.Previous studies have found that MSC-sEV can be used for microRNA delivery into target cells or tissues.It is currently unclear whether microRNA-4465(miR-4465)can target LOXL2 and inhibit HSC activation.Additionally,it is uncertain whether MSC-sEV can be utilized as a gene therapy vector to carry miR-4465 and effectively inhibit the progression of liver fibrosis.This study explored the effect of miR-4465-modified MSC-sEV(MSC-sEVmiR-4465)on LOXL2 expression and liver fibrosis development.The results showed that miR-4465 can bind specifically to the promoter of the LOXL2 gene in HSC.Moreover,MSC-sEVmiR-4465 inhibited HSC activation and collagen expression by downregulating LOXL2 expression in vitro.MSC-sEVmiR-4465 injection could reduce HSC activation and collagen deposition in the CCl4-induced mouse model.MSC-sEVmiR-4465 mediating via LOXL2 also hindered the migration and invasion of HepG2 cells.In conclusion,we found that MSC-sEV can deliver miR-4465 into HSC to alleviate liver fibrosis via altering LOXL2,which might provide a promising therapeutic strategy for liver diseases.
基金This work was supported by the National Research Foundation of Korea(NRF)grant(2018R1A2A1A05077608)the Korea Mouse Phenotyping Project(2014M3A9D5A01073556)the Intelligent Synthetic Biology Center of Global Frontier Project(2011-0031955)funded by the Korea government(MSIT).
文摘Alcoholic liver disease(ALD)represents a wide spectrum of disease from simple steatosis to cirrhosis.Although there have been multiple attempts to treat ALD,its treatment is still based on abstinence from alcohol and using corticosteroids in specified cases.However,nearly 40%of patients with ALD who are in need of treatment are unresponsive to the current treatments,which implies a new paradigm shift for the treatment of ALD.Traditionally,earlier studies have focused on the abnormal metabolism occurring in the hepatocytes as a protagonist in the pathogenesis of ALD.However,increasing evidence suggests that non-parenchymal cells,such as hepatic stellate cells(HSCs),Kupffer cells,liver sinusoidal endothelial cells,and immune cells around the hepatocytes have critical roles in multiple stages of ALD either by direct or indirect cell-to-cell interactions.For instance,in the early stage of ALD,Kupffer cells and HSCs located closely to hepatocytes contribute to the development of alcoholic steatosis and inflammation through the secretion of various inflammatory cytokines(immunologic pathways)and the activation of the endocannabinoid system(metabolic pathways).While the stage of ALD progresses to alcoholic hepatitis and fibrosis,various cell-to-cell interactions with infiltrating immune cells become highly significant at the multicellular level.This review explains the diverse roles of non-parenchymal cells in the progression of ALD,as well as potential therapeutic strategies to treat ALD.
基金supported by the National Natural Science Foundation of China(Nos.81930099,81773664,82130102,92159304,81703585,and 81903651)the Natural Science Foundation of Jiangsu Province(Nos.BK20212011 and BK20180565)+4 种基金the Technology Innovation Project of Nucleic Acid Drug from National Center of Technology Innovation for Biopharmaceuticals(No.NCTIB2022HS01014)the“Double First-Class”University Project(No.CPU2022QZ05)the 111 Project from the Ministry of Education of China and the State Administration of Foreign Expert Affairs of China(Nos.111-2-07 and B17047)the Fundamental Research Funds for the Central Universities of China(No.2632022ZD11)the Open Project of State Key Laboratory of Natural Medicines(No.SKLNMZZ202017),China.
文摘An effective therapeutic regimen for hepatic fibrosis requires a deep understanding of the pathogenesis mechanism.Hepatic fibrosis is characterized by activated hepatic stellate cells(aHSCs)with an excessive production of extracellular matrix.Although promoted activation of HSCs by M2 macrophages has been demonstrated,the molecular mechanism involved remains ambiguous.Herein,we propose that the vitamin D receptor(VDR)involved in macrophage polarization may regulate the communication between macrophages and HSCs by changing the functions of exosomes.We confirm that activating the VDR can inhibit the effect of M2 macrophages on HSC activation.The exosomes derived from M2 macrophages can promote HSC activation,while stimulating VDR alters the protein profiles and reverses their roles in M2 macrophage exosomes.Smooth muscle cell-associated protein 5(SMAP-5)was found to be the key effector protein in promoting HSC activation by regulating autophagy flux.Building on these results,we show that a combined treatment of a VDR agonist and a macrophage-targeted exosomal secretion inhibitor achieves an excellent anti-hepatic fibrosis effect.In this study,we aim to elucidate the association between VDR and macrophages in HSC activation.The results contribute to our understanding of the pathogenesis mechanism of hepatic fibrosis,and provide potential therapeutic targets for its treatment.
基金funded by the Prometheus USA(www.prometheususa.org)and Vietnam National Foundation for Science&Technology Development(NAFOSTED)under grant number 108.05e2017.30.
文摘Background:Biliary atresia is a rare congenital bile duct disease that is the leading cause of liver fibrosis in neonates.Granulocyte colony-stimulating factor(GCSF)is a potential therapy for hepatocellular diseases,but data on GCSF for cholestatic conditions remain limited.Materials and methods:The current study examines the role of GCSF in improving bile duct obstruction in mice.Two doses were administered:10.0 mg/kg/day and 61.5 mg/kg/day,which is the animal equivalent dose of 5.0 mg/kg in humans.Seven days(D7)after bile duct ligation(BDL),Swiss mice were treated with phosphate buffered saline or GCSF for 5 days.The intrahepatic adaptive response of BDL mice was evaluated on postsurgical days D12,D19,and D26.Results:Treatment with 61.5 mg/kg of GCSF resulted in a significant increase in circulating leukocytes and neutrophils on D12.Amelioration of liver injury,as shown by reduced aspartate aminotransferase levels,increased albumin levels and survival rate,as well as reduced intrahepatic inflammation and hepatic myeloperoxidase expression,downregulated ductular proliferation,periportal fibroblast activation,and fibrosis,enhanced expressions of hepatocyte growth factor,peroxisome proliferator-activated receptoralpha,and ki67,and suppressed expression of cleaved caspase-3 protein,was noted after treatment with 61.5 mg/kg of GCSF.Additionally,GCSF treatment was associated with an increased number of intrahepatic cd3-Sca1tc-Kitt bone marrow cells.
