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

doi:10.1007/s11684-024-1079-1

Front. Med.

2024, Vol. 18

Issue (3) : 538-557 https://doi.org/10.1007/s11684-024-1079-1

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

Yue Yuan¹, Jiaxuan Li¹, Xun Lu^2,³, Min Chen¹, Huifang Liang^2,³, Xiao-ping Chen^2,³, Xin Long^2,³, Bixiang Zhang^2,³, Song Gong⁴, Xiaowei Huang¹, Jianping Zhao^2,³(

), Qian Chen¹(

)

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

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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

Corresponding Author(s): Jianping Zhao,Qian Chen

Just Accepted Date: 12 April 2024 Online First Date: 20 May 2024 Issue Date: 17 June 2024

Cite this article:

Yue Yuan,Jiaxuan Li,Xun Lu, et al. Autophagy in hepatic progenitor cells modulates exosomal miRNAs to inhibit liver fibrosis in schistosomiasis[J]. Front. Med., 2024, 18(3): 538-557.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-024-1079-1
https://academic.hep.com.cn/fmd/EN/Y2024/V18/I3/538

Fig.1 Activation of HPCs during S. japonicum-induced liver fibrosis. (A) Representative images of liver sections from human patients with and without S. japonicum infection stained with hematoxylin and eosin (H&E) and Sirius red staining (n = 5). Scale bars, 100 μm. (B) Immunohistochemical staining for CK19, OV-6, and ɑSMA (n = 5). Scale bars, 100 μm. (C) Immunofluorescence staining for CK19 (green), EpCAM (red), and SOX9 (magenta) in the liver sections from mice with S. japonicum infection, compared with those from uninfected mice (n = 5). Scale bars, 50 μm. Datas are shown as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001; ns, not significant.

Fig.2 Effects of HPCs on HSCs activation in vitro. (A) Protocol for extraction and separation of HPCs from livers of the control or S. japonicum-infected mice (0 w, 4 w, 6 w and 8 w). Primary HPCs were cocultured with primary mouse HSCs. (B) ɑSMA was detected by WB in primary HSCs cocultured with conditioned medium (CM) from EpCAM⁺ HPCs (n = 3). (C) ɑSMA and Col1ɑ1 were assessed by qPCR in HSC-T6 cells cocultured with the CM from LE/6 cells treated with SEA (20 µg/mL) or PBS for 24 h (n = 3). (D) Proteomic analysis was performed to determine the number of differentially expressed proteins in LE/6 cells between the CON and SEA-treated group (n = 3) (P < 0.05 and fold change > 1.2 or < 0.83). (E) Heatmap analysis of differentially expressed proteins (DEG) in LE/6 cells between the CON and SEA group (n = 3) according to the result of proteomic analysis (P < 0.05). (F) Volcano blot showing differentially expressed genes from the protein sequencing data of LE/6 cells. (G) Top 10 KEGG pathways related to DEGs in LE/6 cells. The horizontal axis represents the number of DEGs included in the terms, and the vertical axis is arranged in descending order of the number of DEGs. The red box indicates the pathways associated with autophagy. Data are presented as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001; ns, not significant; w, week.

Fig.3 Impaired autophagy degradation and lysosomal dysfunction in HPCs upon SEA stimulation. (A) Immunoblot of LC3B and P62 in LE/6 cells treated with PBS, SEA (20 µg/mL) or CQ (20 µmol/L) for 24 h (n = 3). (B) IF staining of LE/6 cells transfected with an mRFP-GFP-LC3B reporter construct and treated with SEA or CQ. (C) The quantification of GFP and RFP signals from 3 to 5 independent tests; t-test. (D) Autophagosome-lysosome fusion was assessed by measuring the colocalization of LAMP1-positive lysosomes with LC3-positive autophagosomes in LE/6 cells treated with PBS, SEA, rapamycin (10 µmol/L) or bafilomycin A1 (10 nmol/L) for 24 h (n = 3). Scale bar, 10 µm. (E) The mRNA levels of the lysosomal proton pump subunits (ATP6V0C, ATP6V1H, ATP6V0E1, ATP6V0B) were examined in LE/6 cells. (F) LysoTracker Red staining of LE/6 cells. The red color indicates lysosomes; the blue color indicates the nucleus. Each group was randomly selected for quantitative analysis by ImageJ software (n = 6–12). Scale bar, 10 µm. (G) Immunoblot of CTSB and CTSD in LE/6 cells. (H) Cytoplasmic fractions and nuclear fractions of LE/6 cells were extracted and assessed for TFEB by WB. (I) P62 was assessed in LE/6 cells by WB. Data are presented as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001; ns, not significant.

Fig.4 Blocking autophagy ameliorates HPC-associated fibrosis during S. japonicum infection. (A) IF staining to detect the colocalization of CK19 (green) and P62 (red) in the liver sections from mice with or without S. japonicum infection. Scale bar, 100 µm. (B) The protein levels of LC3B and p62 were assessed by WB in primary HPCs from infected or uninfected mice (n = 4–6). Mice were infected percutaneously with 20 S. japonicum cercariae or remained uninfected. At 4 weeks post-infection, the infected mice were intraperitoneally injected with CQ, Tre or PBS. The mice were necropsied at 8 weeks post-infection. (C) Time schedule for the parasite infection, administration of CQ, Tre, and PBS, and sample withdrawal. (D) Serum ALT and AST levels were measured (n = 5–7/group). (E) H&E and Sirius red staining of liver sections (n = 6–7/group). Scale bar, 200 μm. (F) ɑSMA and Col1ɑ1 proteins were determined by WB. Image density was quantified using ImageJ analysis and normalized to that of GAPDH (n = 5–7/group). (G) The expression of ɑSMA was assessed by WB in primary HSCs cocultured with primary HPCs of normal or infected mice. Data are presented as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001; ns, not significant; w, week.

Fig.5 HPCs inhibit S. japonicum-induced liver fibrosis by secreting anti-fibrotic EVs. (A) Transmission electron microscopy (TEM) was used to confirm the size and classic structure of the EVs produced by LE/6 cells pretreated with SEA (SEA-EVs) or PBS (CON-EVs) for 24 h. (B) WB was performed to assess the EV markers (TSG101, Alix, and CD63) and the negative EV marker Calnexin in CON-EVs or SEA-EVs. (C) NTA was performed to characterize the particle size and concentration of EVs. (D) HSC-T6 cells cocultured with PBS, CON-EVs or SEA-EVs were examined by WB for ɑSMA. (E) HSC-T6 cells cultured with CM or EV-depleted CM from LE/6 cells for 24 h were examined by WB for ɑSMA. Image density was quantified using ImageJ analysis and normalized to that of GAPDH (n = 3/group). (F) HSC-T6 cells cultured with CM from LE/6 cells pretreated with SEA or GW4869 (10 µmol/L, 4 h) were examined by WB for ɑSMA (n = 3/group). Rats were infected percutaneously with 100 S. japonicum cercariae. At 5 weeks post-infection, the infected rats were treated with CON-EVs or SEA-EVs and were necropsied at 8 weeks post-infection. (G) The serum ALT and AST levels were measured (n = 6/group). (H) Representative images of liver sections stained with H&E, Sirius red, and IHC for ɑSMA. The size of the hepatic granulomas and the percentage of Sirius red staining were measured (n = 5–8/group). Scale bar, 200 μm. (I) Collagen content in the livers was determined as hydroxyproline content (n = 5–6/group). (J) ɑSMA and Col1ɑ1 protein levels in liver tissues were determined by Western blotting (n = 6/group). Data are presented as the mean ± SD followed by one-way ANOVA. *P < 0.05, **P < 0.01, ***P < 0.001; ns, not significant.

Fig.6 Impaired autophagy degradation reduced the secretion of miRNAs in HPC-derived EVs. (A) Principal component analysis (PCA) of miRNA components in EVs showing segregation of SEA-EVs (n = 3) from CON-EVs (n = 3). (B) A heatmap represents the levels (log₂(fold change (FC))) of 36 differentially secreted miRNAs in SEA-EVs compared with CON-EVs. Blue indicates downregulation in SEA-EVs, whereas red indicates upregulation. (C) Volcano plot of the SEA-EV group versus the CON-EV group. The x-axis represents log₂(FC) and the y-axis represents –lgP. Red dots represent genes with differential expression (|FC| ≥ 2, P < 0.05). (D) Relative expression of miR-1306-3p, miR-493-3p, and miR-34a-5p in HSC-T6 cells stimulated with PBS, CON-EVs or SEA-EVs (n = 3). (E) Verification of the relative expression of the three miRNAs in 200 µg CON-EVs and 200 µg SEA-EVs (n = 3). The relative expression of the three miRNAs was examined in EVs (C) and donor LE/6 cells (D) after treatment with CQ or Tre for 24 h (n = 3). (H) Representative microscope images from LE/6 cells expressing GFP-Rab5Q79L. Cells were transfected with Cy3-miR-1306-3p (upper row), Cy3-miR-493-3p (median row), or Cy3-miR-34a-3p (upper row). Selected areas were enlarged. Scale bar, 5 µm. The percentage of Cy3-miR-1306-3p, Cy3-miR-493-3p or Cy3-miR-34a-3p -positive GFP-Rab5Q79L rings in all GFP-Rab5Q79L rings is presented on the left side of the graph. Each circle represents a cell (n = 3–5). (I) The expression levels of three miRNAs in EVs (100 µg) from primary mouse HPCs were examined by qPCR (n = 3/group). Data are presented as the mean ± SD followed by one-way ANOVA. *P < 0.05, **P < 0.01, ***P < 0.001; ns, not significant.

Fig.7 Active effect of miR-1306-3p on HSCs. (A) qPCR was performed to assess the levels of miR-1306-3p, miR-493-3p, and miR-34a-5p in HSC-T6 cells transfected with miR-1306-3p, miR-493-3p, and miR-34a-5p mimic, respectively (n = 3). (B) WB was performed to assess the fibrotic markers of HSC-T6 cells transfected with the three miRNA mimics. (C) WB was performed to assess the expression of ɑSMA in the HSC-T6 cells treated with CON-EVs/SEA-EVs or SEA-EVs derived from LE/6 cells transfected with the three miRNAs mimics. (D) With two miRNA databases (miRanda and TargetScan Release 3.1), the potential target genes of miR-1306-3p were predicted. The Foxo3 gene is highlighted in red. (E) qPCR was performed to assess the level of Foxo3 in the HSC-T6 cells cocultured with SEA-EVs or CON-EVs. (F) The protein and (G) mRNA levels of Foxo3 in the HSC-T6 cells with miR-1306-3p mimics or inhibitors (n = 3). (H) Luciferase activity of the wild-type (WT) Foxo3-3′UTR reporter gene and mutant type (mut) Foxo3-3′UTR reporter gene in HSC-T6 cells (n = 3). Cells were transiently transfected either with miR-1306-3p mimic or negative control. The target region of miR-1306-3p in the 3′UTR of Foxo3 is shown on the upper part of the graph. Graph bars represent the SEM, one-way ANOVA or t-test for comparison. *P < 0.05, **P < 0.01, ***P < 0.001; ns, not significant.

Fig.8 Proposed mechanism. HPCs are located in the canals of Herring to receive stimulation by SEA released from S. japonicum eggs while they penetrate into the portal system. SEA impaired autophagic degradation mediated by lysosomal dysfunction in HPCs. The impaired autophagy degradation decreased the sorting of three miRNAs (miR-1306-3p, miR-493-3p, and miR-34a-5p) from the cytoplasm into MVBs, subsequently leading to the decreased expression of these three miRNAs in EVs released from HPCs. The secreted EVs inhibited HSC activation, and finally alleviated the progression of liver fibrosis in schistosomiasis. Specially, the most obvious changed miRNA, miR-1306-3p, modulates HSCs by targeting the antifibrotic gene Foxo3.

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