Knockdown of miR-23, miR-27, and miR-24 Alters Fetal Liver Development and Blocks Fibrosis in Mice

• Published in: Gene expression Vol. 17; no. 2; pp. 99 - 114
• Main Authors: Rogler, Charles E., Matarlo, Joe S., Kosmyna, Brian, Fulop, Daniel, Rogler, Leslie E.
• Format: Journal Article
• Language: English
• Published: Elmsford, NY Cognizant Communication Corporation 10.02.2017; Xia & He Publishing
• Subjects: Actins - genetics; Alb/TGF-β1; Animals; Bile ducts; Bile Ducts - pathology; Binding sites; Cell activation; Cell differentiation; Cell Differentiation - genetics; Cell Fate; Cell Line; Cell Proliferation - genetics; Clusters; Cytokeratin; Differentiation; Differentiation (biology); Drug dosages; Females; Fetal Development - genetics; Fetuses; Fibrosis; Gene expression; Growth factors; Hepatic Progenitors; Hepatic Stellate Cells - pathology; Hepatocytes - pathology; Injection; Liver; Liver - pathology; Liver Cirrhosis - genetics; Liver Cirrhosis - pathology; Liver Fibrosis; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microrna; MicroRNAs; MicroRNAs - genetics; Mir-23; Mir-24; Mir-27; miRNA; Mutagenesis; Mutation; Organogenesis - genetics; Parenchyma; Proteins; Signal transduction; Smad4 protein; Transforming Growth Factor beta1; Transforming growth factor-b; Transforming growth factor-b1; Transgenic animals; Transgenic mice
• ISSN: 1052-2166; 1555-3884
• DOI: 10.3727/105221616X693891

MicroRNAs (miRNAs) regulate cell fate selection and cellular differentiation. miRNAs of the miR23b polycistron (miR-23b, miR-27b, and miR-24) target components of the TGF-β signaling pathway and affect murine bile ductular and hepatocyte cell fate selection in vitro. Here we show that miR-23b polycistron miRNAs directly target murine Smad4, which is required for TGF-β signaling. Injection of antagomirs against these miRNAs directly into E16.5 murine fetuses caused increased cytokeratin expression in sinusoids and primitive ductular elements throughout the parenchyma of newborn mice. Similar antagomir injection in newborn mice increased bile ductular differentiation in the liver periphery and reduced hepatocyte proliferation. Antagomir injection in newborn Alb/TGF-β1 transgenic mice that develop fibrosis inhibited the development of fibrosis, and injection of older mice caused the resolution of existing fibrosis. Furthermore, murine stellate cell activation, including ColA1 and ACTA2 expression, is regulated by miR-23b cluster miRNAs. In summary, knockdown of miR-23b cluster miRNAs in fetal and newborn liver promotes bile duct differentiation and can block or revert TGF-β-induced liver fibrosis that is dependent on stellate cell activation. These data may find practical application in the highly needed development of therapies for the treatment of fibrosis.