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.
摘要：
血吸虫感染是肝纤维化的主要原因之一。已经确定了肝祖细胞（HPCs）在肝纤维化发病机理中的新兴作用。然而，HPCs在血吸虫病肝纤维化中的作用机制尚不清楚.这项研究研究了HPCs中的自噬如何通过调节外泌体miRNA影响血吸虫病诱导的肝纤维化。通过免疫组织化学（IHC）和免疫荧光（IF）染色在日本血吸虫感染的患者和小鼠的纤维化肝脏中验证了HPCs的激活。通过将HPCs与肝星状细胞（HSC）共培养，并通过蛋白质组学分析和体外表型测定评估HPCs中的自噬水平，我们发现这些活化的HPCs的自噬降解受损是由溶酶体功能障碍介导的。自噬抑制剂氯喹（CQ）阻断自噬可显着减少日本血吸虫感染小鼠的肝纤维化和肉芽肿形成。进一步分离HPC分泌的细胞外载体(EV)并通过miRNA测序进行研究。miR-1306-3p,miR-493-3p,和miR-34a-5p被鉴定，由于HPCs的自噬受损，它们在电动汽车中的分布受到抑制，这有助于抑制HSC激活。总之,我们发现，HPC激活后自噬过程的改变可能通过调节外泌体miRNA释放和抑制血吸虫病HSC激活来预防肝纤维化。靶向自噬降解过程可能是血吸虫感染期间肝纤维化的治疗策略。
