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

Abstract

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.

Keywords

schistosomiasis / hepatic progenitor cell / autophagy / extracellular vesicle / fibrosis / miRNA

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Acknowledgements

The authors thank Yan Wang and Yuan Sun (Institute of Hydrobiology, Chinese Academy of Sciences) for technical assistance with the in vivo imaging system. This work was financially supported by the National Natural Science Foundation of China (No. 82003403 (Jianping Zhao), No. 81974077, and No. 82170633 (Qian Chen)).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1079-1 and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest Yue Yuan, Jiaxuan Li, Xun Lu, Min Chen, Huifang Liang, Xin Long, Bixiang Zhang, Song Gong, Xiaowei Huang, Jianping Zhao, and Qian Chen declare that they have no conflict of interest. Xiao-ping Chen is one of Editors-in-Chief of Frontiers of Medicine, who was excluded from the peer-review process and all editorial decisions related to the acceptance and publication of this article. Peer-review was handled independently by the other editors to minimise bias.

The study was approved by the Ethics Committee of Tongji Hospital (TJ-IRB20231140) (HUST, Wuhan, China). Additional informed consent was obtained from all patients whose identifying information is included in this article. All institutional and national guidelines for the care and use of laboratory animals were followed.

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