Autophagy in hepatic progenitor cells modulates exosomal miRNAs to inhibit liver fibrosis in schistosomiasis  

作　　者：Yue Yuan Jiaxuan Li Xun Lu Min Chen Huifang Liang Xiao-ping Chen Xin Long Bixiang Zhang Song Gong Xiaowei Huang Jianping Zhao Qian Chen 

机构地区：[1]Division of Gastroenterology,Department of Internal Medicine at Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China [2]Hepatic Surgery Center,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China [3]Hubei Key Laboratory of Hepato–Pancreato–Biliary Diseases,Wuhan,430030,China [4]Department of Trauma Surgery,Tongji Trauma Center,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China

出　　处：《Frontiers of Medicine》2024年第3期538-557,共20页医学前沿（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.82003403(Jianping Zhao),No.81974077,and No.82170633(Qian Chen)).

摘　　要：Schistosoma infection is one of the major causes of liver fibrosis.Emerging roles of hepatic progenitor cells(HPCs)in the pathogenesis of liver fibrosis have been identified.Nevertheless,the precise mechanism underlying the role of HPCs in liver fibrosis in schistosomiasis remains unclear.This study examined how autophagy in HPCs affects schistosomiasis-induced liver fibrosis by modulating exosomal miRNAs.The activation of HPCs was verified by immunohistochemistry(IHC)and immunofluorescence(IF)staining in fibrotic liver from patients and mice with Schistosoma japonicum infection.By coculturing HPCs with hepatic stellate cells(HSCs)and assessing the autophagy level in HPCs by proteomic analysis and in vitro phenotypic assays,we found that impaired autophagy degradation in these activated HPCs was mediated by lysosomal dysfunction.Blocking autophagy by the autophagy inhibitor chloroquine(CQ)significantly diminished liver fibrosis and granuloma formation in S.japonicum-infected mice.HPC-secreted extracellular vehicles(EVs)were further isolated and studied by miRNA sequencing.miR-1306-3p,miR-493-3p,and miR-34a-5p were identified,and their distribution into EVs was inhibited due to impaired autophagy in HPCs,which contributed to suppressing HSC activation.In conclusion,we showed that the altered autophagy process upon HPC activation may prevent liver fibrosis by modulating exosomal miRNA release and inhibiting HSC activation in schistosomiasis.Targeting the autophagy degradation process may be a therapeutic strategy for liver fibrosis during Schistosoma infection.

关 键 词：SCHISTOSOMIASIS hepatic progenitor cell AUTOPHAGY extracellular vesicle fibrosis miRNA 

分 类 号：R532.2[医药卫生—内科学]