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The transcription factor Klf5 is essential for intrahepatic biliary epithelial tissue remodeling against liver injury

岡田, 甫 東京大学 DOI:10.15083/0002001410

2021.09.08

概要

Under various conditions of liver injury, the intrahepatic biliary epithelium undergoes dynamic tissue expansion and remodeling, a process known as ductular reaction. Mouse genetic models defective in inducing such a tissue remodeling process are more susceptible to liver injury, suggesting its crucial role in liver regeneration. However, the molecular mechanisms regulating the biliary epithelial cell (BEC) dynamics in ductular reaction remain largely unclear. Here, we demonstrated that the transcription factor Krüppel-like factor 5 (Klf5) is highly enriched in mouse liver BECs and it plays a key role in regulating the ductular reaction, specifically under cholestatic injury conditions. Although mice lacking Klf5 in the entire liver epithelium, including both hepatocytes and BECs (Klf5 LKO mice), did not exhibit any apparent phenotype in the hepatobiliary system under normal conditions, they exhibited significant defect in biliary epithelial tissue remodeling upon 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced cholangitis, concomitantly with exacerbated cholestasis and reduced survival rate. In contrast, mice lacking Klf5 solely in hepatocytes did not exhibit any comparable phenotype, confirming its specific role in BECs. Transcriptome analyses of BECs isolated from the Klf5 LKO mouse liver revealed that expression of cell cycle-related genes was primarily affected. Accordingly, immunostaining analysis using Ki67 showed that the level of BEC proliferation upon injury was significantly reduced in the Klf5 LKO mice. These results indicate that Klf5 plays a critical role in biliary epithelial tissue expansion and remodeling through induction of BEC proliferation, thereby contributing to liver regeneration.

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