Interleukins‐17 and 27 promote liver regeneration by sequentially inducing progenitor cell expansion and differentiation

Abstract

Liver progenitor cells (LPCs)/ductular reactions (DRs) are associated with inflammation and implicated in the pathogenesis of chronic liver diseases. However, how inflammation regulates LPCs/DRs remains largely unknown. Identification of inflammatory processes that involve LPC activation and expansion represent a key step in understanding the pathogenesis of liver diseases. In the current study, we found that diverse types of chronic liver diseases are associated with elevation of infiltrated interleukin (IL)‐17‐positive (+) cells and cytokeratin 19 (CK19)+ LPCs, and both cell types colocalized and their numbers positively correlated with each other. The role of IL‐17 in the induction of LPCs was examined in a mouse model fed a choline‐deficient and ethionine‐supplemented (CDE) diet. Feeding of wild‐type mice with the CDE diet markedly elevated CK19+Ki67+ proliferating LPCs and hepatic inflammation. Disruption of the IL‐17 gene or IL‐27 receptor, alpha subunit (WSX‐1) gene abolished CDE diet‐induced LPC expansion and inflammation. In vitro treatment with IL‐17 promoted proliferation of bipotential murine oval liver cells (a liver progenitor cell line) and markedly up‐regulated IL‐27 expression in macrophages. Treatment with IL‐27 favored the differentiation of bipotential murine oval liver cells and freshly isolated LPCs into hepatocytes. Conclusion: The current data provide evidence for a collaborative role between IL‐17 and IL‐27 in promoting LPC expansion and differentiation, respectively, thereby contributing to liver regeneration. (Hepatology Communications 2018;2:329‐343)

Synthetic liver fibrotic niche extracts achieve in vitro hepatoblasts phenotype enhancement and expansion

“…To facilitate the understanding of NE and their application for HBs expansion, we attempted to resolve the ECM components and factors in the P2 NE which contributed to the HBs phenotype maintenance and expansion, in order to reconstitute the fibrotic niches with defined NE components ( Figure 6 A).Quantitative proteomics analysis for the P2 and F7 NE ingredients indicated significant up-regulation of 2 types of ECM components (i.e., collagen type III and collagen type IV) and 2 types of inflammatory factors (i.e., IL-18 and M-CSF) ( Table S2 ). As previously shown by RNA-seq analysis ( Figures 3 E and S6 A), IL-17 signaling pathway was up-regulated in the fibrotic niche and IL-17 treatment was reported to promote proliferation of bipotential murine oval cells—a liver progenitor-like cell ( Guillot et al., 2018 ). Therefore, IL-17 was also introduced into the combinatorial groups of the defined ECM and factors for HBs expansion.…”

Human Induced Pluripotent Stem Cell-Derived Macrophages Ameliorate Liver Fibrosis

“…Consistent with the trend we observed in total tissue gene expression analysis, TIMP-1 expression decreased more noticeably in the iPSC-M2 treated group compared with CCl 4 treatment alone. Levels of IL-17A and IL-27, two cytokines that are reported to have a collaborative role in liver regeneration 28 were elevated in liver of mice treated with human iPSC-M2 compared with CCl 4 treatment alone.…”

Deficiency in interleukin‐10 production by M2 macrophages in eosinophilic chronic rhinosinusitis with nasal polyps

“…M0 macrophages were polarized into M1 macrophages by further stimulation with LPS and IFN‐γ at 100 ng/mL, or into M2 macrophages by stimulation with IL‐4 at 40 ng/mL and IL‐13 at 20 ng/mL, for 48 hours . After polarization, M2 macrophages were stimulated with poly I:C (25 μg/mL), IFN‐γ (100 ng/mL), TNF‐α (25 ng/mL), IL‐1β (100 ng/mL), IL‐6 (100 ng/mL), or IL‐17A (100 ng/mL) for 6 hours . After stimulation, cells were harvested and subjected to quantitative PCR analysis to measure CD163 and IL‐10 expression.…”