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Knockdown of miR-23, miR-27, and miR-24 Alters Fetal Liver Development and Blocks Fibrosis in Mice
Abstract:
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.
Insights
MicroRNAs regulate liver cell fate and fibrosis. Targeting miR-23b cluster miRNAs promotes bile duct differentiation and reverses liver fibrosis by inhibiting stellate cell activation.
Area of Science:
- Molecular Biology
- Developmental Biology
- Hepatology
Background:
- MicroRNAs (miRNAs) are crucial regulators of cell fate and differentiation.
- The miR-23b polycistron (miR-23b, miR-27b, miR-24) influences TGF-β signaling and liver cell fate.
- Smad4 is a key component of the TGF-β signaling pathway.
Purpose of the Study:
- To investigate the role of miR-23b cluster miRNAs in liver development and fibrosis.
- To determine if these miRNAs directly target Smad4.
- To evaluate the therapeutic potential of targeting these miRNAs in liver fibrosis.
Main Methods:
- In vitro studies on murine bile ductular and hepatocyte cell lines.
- In vivo antagomir injection into fetal and newborn mice.
- Analysis of gene expression (cytokeratin, ColA1, ACTA2) and cell proliferation.
- Studies in Alb/TGF-β1 transgenic mice with induced liver fibrosis.
Main Results:
- miR-23b cluster miRNAs directly target Smad4, a TGF-β signaling component.
- Antagomir treatment in fetal/newborn mice increased bile duct differentiation and decreased hepatocyte proliferation.
- Antagomir treatment inhibited fibrosis development in transgenic mice and resolved existing fibrosis in older mice.
- miR-23b cluster miRNAs regulate murine stellate cell activation.
Conclusions:
- Knockdown of miR-23b cluster miRNAs promotes bile duct differentiation in the developing liver.
- Targeting miR-23b cluster miRNAs can block or reverse TGF-β-induced liver fibrosis.
- These findings suggest potential therapeutic applications for liver fibrosis treatment.
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