IL‐8 induces transdifferentiation of mature hepatocytes toward the cholangiocyte phenotype

• Published in: FEBS open bio Vol. 9; no. 12; pp. 2105 - 2116
• Main Authors: Sasaki, Tokio, Suzuki, Yuji, Kakisaka, Keisuke, Wang, Ting, Ishida, Kazuyuki, Suzuki, Akiko, Abe, Hiroaki, Sugai, Tamotsu, Takikawa, Yasuhiro
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2019; John Wiley and Sons Inc; Wiley
• Subjects: Aged; Bile; Biopsy; Cell adhesion & migration; Cell Differentiation; Cell Lineage; Cell Transdifferentiation - physiology; cholangiocyte; Cytokines; Epithelial Cells; Experiments; Female; Genotype & phenotype; Hepatitis; Hepatocytes; Hepatocytes - metabolism; Hepatocytes - physiology; Humans; Interleukin-8 - metabolism; Interleukin-8 - physiology; interleukin‐8; Liver - metabolism; Liver - physiology; Liver diseases; Male; mature hepatocyte; Middle Aged; Patients; Phenotype; Phenotypes; Plasma; Progenitor cells; Proteins; Sox9 protein; SOX9 Transcription Factor - metabolism; SOX9 Transcription Factor - physiology; Sry HMG box protein 9; Stem Cells; transdifferentiation; United States > US; Japan; transdifferentiation; cholangiocyte; mature hepatocyte; interleukin-8; Sry HMG box protein 9
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.12750

The adult mammalian liver exhibits a remarkable regenerative capacity, with different modes of regeneration according to the type and extent of injury. Hepatocyte–cholangiocyte biphenotypic liver progenitor cell populations appear under conditions of excessive injury. It has been reported that mature hepatocytes can transdifferentiate toward a cholangiocyte phenotype and be a cellular source of progenitor cell populations. Here, we determined that among various plasma cytokines, interleukin (IL)‐8 levels were significantly elevated in acute liver failure and severe acute liver injury patients. In vitro assays revealed that administration of IL‐8 homologues increases the expression of Sry HMG box protein 9 (SOX9). In liver biopsies of acute liver injury patients, we observed the appearance of SOX9‐positive biphenotypic hepatocytes accompanied by elevation of plasma IL‐8 levels. Our results suggest that IL‐8 regulates the phenotypic conversion of mature hepatocytes toward a cholangiocyte phenotype. Interleukin (IL)‐8 treated mouse mature hepatocytes expressed Sry HMG box protein 9 (SOX9), a bile duct‐associated marker. In liver biopsies of acute liver injury patients, SOX9‐positive biphenotypic hepatocytes appeared in the liver parenchyma which is accompanied by elevation of plasma IL‐8 levels. Our results suggest that IL‐8 regulates the phenotypic conversion of mature hepatocytes toward a cholangiocyte phenotype.