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Exosomal miR-183-5p from human hepatocyte-derived liver progenitor-like cells promotes liver regeneration during acute liver failure

ABSTRACT: Hepatocyte-derived liver progenitor-like cells (HepLPCs) can reversibly differentiate into mature hepatocytes and play important roles in liver regeneration following acute liver failure. However, the mechanisms by which HepLPCs exert these regulatory effects are unclear. Herein, we report that HepLPCs participate in reinitiating liver regeneration and improving survival during acute liver failure, at least in part, via miRNA-183-5p, which is released from HepLPCs in extracellular vesicles. Thus, these findings may identify novel targets and strategies for the treatment of acute liver failure.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226645 | GEO | 2024/12/06

REPOSITORIES: GEO

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Project description:The liver has inherent regenerative capacity via mitotic division of mature hepatocytes. However, if the hepatic loss is massive or mature hepatocyte proliferation is impaired by chronic liver injury, HSPC are activated to support liver regeneration. Access to liver tissue from 4 patients who underwent liver transplantation for hepatitis B virus (HBV)- associated acute liver failure (ALF) provided us with the opportunity to investigate the molecular mechanisms of liver regeneration in humans by means of gene expression profiling and immunohistochemistry (IHC). Gene expression profiling of 17 liver specimens from the 4 ALF cases and individual liver specimens from 10 liver donors documented a distinct gene signature for ALF. However, unsupervised multidimensional scaling and hierarchical clustering identified two-well defined clusters that segregated according to the histopathological severity, i.e. massive hepatic necrosis (MHN; 2 patients) and submassive hepatic necrosis (SHN; 2 patients). We found that ALF is characterized by a strong hepatic stem/progenitor cell (HSPC) gene signature, as also confirmed by IHC, along with ductular reaction, both of which are more prominent in MHN. Interestingly, no evidence of further lineage differentiation was seen in MHN, whereas in SHN we detected cells with hepatocyte-like morphology. Strikingly, ALF was associated with a strong tumorigenesis gene signature. MHN had the greatest upregulation of cancer stem cell genes (EpCAM, CK19 and CK7), whereas the most upregulated genes in SHN were related to cellular growth and proliferation (AKR1B10, NQO1, RRM2, SFN, TOP2A, CCNB1, CDC20, ANLN and KI67). The extent of liver necrosis correlated with an overriding fibrogenesis gene signature, reflecting the wound healing process. Conclusion: Our data provide evidence of marked HSPC cell activation and fibrogenesis in HBV-associated ALF, which positively correlate with the extent of liver necrosis. Moreover, we detected a strong tumorigenesis gene signature in ALF, which underlines the relationship between liver regeneration and liver cancer. Liver samples were obtained from explanted liver of four patients with HBV-associated acute liver failure (4-5 samples per liver) and 10 individual normal liver donors and gene expression profiling was used to establish a molecular definition of this disease. This dataset is part of the TransQST collection.

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Exosomal miR-183-5p from human hepatocyte-derived liver progenitor-like cells promotes liver regeneration during acute liver failure

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