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miR149-5p: A hepatocyte EXOmotif sequence containing microRNA that attenuates liver fibrosis by specifically
Ji-Chao Zhou1, An-Jian Xu2, Jing Miao1
1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Introduction:
Liver fibrosis is a progressive pathological process driven by liver injury, including viral hepatitis and metabolic dysfunction-associated steatohepatitis (MASH), and can progress to cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Hepatocyte-hepatic stellate cell (HSC) crosstalk plays a central role in disease progression, but its regulatory mechanisms remain incompletely understood.
Objectives:
This study aimed to define hepatocyte-HSC crosstalk in liver fibrosis mediated by microRNA-149-5p (miR-149-5p) signaling and to explore its potential as a therapeutic target for intervention.
Methods:
Differentially expressed exosomal microRNAs were identified by RNA sequencing of hepatocyte-derived exosomes from fibrotic and control livers. Functional screening using collagen type I alpha 1 chain (COL1A1) reporter assays identified miR-149-5p as an anti-fibrotic candidate. Exosome-mediated intercellular communication was confirmed using co-culture systems and confirmed by tumor susceptibility 101 (TSG101) silencing. Liver fibrosis was induced by bile duct ligation (BDL) and thioacetamide (TAA) in mice. Therapeutic effects were evaluated using AAV-mediated hepatocyte-specific overexpression and miR-149-5p agomir administration.
Results:
miR-149-5p was selectively enriched in hepatocyte-derived exosomes via a CCUC-based EXOmotif and directly targeted PDGFRB in HSCs, thereby inhibiting HSC activation, proliferation, and collagen deposition without affecting hepatocyte function. During fibrosis progression, PU.1 bound to the miR-149-5p promoter and suppressed its transcription, leading to reduced exosomal miR-149-5p delivery and consequent PDGFRB derepression in HSCs. Both AAV-mediated overexpression and systemic miR-149-5p agomir administration significantly attenuated BDL- and TAA-induced liver fibrosis, as evidenced by reduced collagen deposition, decreased hydroxyproline content, and downregulation of HSC activation markers.
Conclusion:
The PU.1 (hepatocyte)-miR-149-5p (exosome)-PDGFRB (HSC) axis represents a key regulatory pathway in liver fibrosis, wherein PU.1 represses miR-149-5p transcription in hepatocytes, leading to EXOmotif-dependent reduction of exosomal miR-149-5p delivery and consequent derepression of PDGFRB in HSCs, thereby promoting HSC activation and fibrosis progression. Importantly, miR-149-5p agomir administration offers a promising therapeutic strategy for liver fibrosis.
Insights
Researchers identified a key pathway involving microRNA-149-5p (miR-149-5p) in liver fibrosis. This pathway, regulated by PU.1 and targeting PDGFRB in hepatic stellate cells (HSCs), shows promise for new anti-fibrotic therapies.
Area of Science:
- Hepatology and molecular biology
- Cellular signaling and intercellular communication
- Biomarker discovery and therapeutic development
Background:
- Liver fibrosis is a severe condition driven by liver injury, potentially leading to cirrhosis, liver failure, and cancer.
- Hepatocyte-hepatic stellate cell (HSC) crosstalk is crucial in fibrosis progression, but its regulatory mechanisms require further elucidation.
Purpose of the Study:
- To define the role of microRNA-149-5p (miR-149-5p) in hepatocyte-HSC crosstalk during liver fibrosis.
- To investigate miR-149-5p signaling as a potential therapeutic target for liver fibrosis intervention.
Main Methods:
- RNA sequencing identified differentially expressed exosomal microRNAs in fibrotic liver hepatocytes.
- Functional assays confirmed miR-149-5p's anti-fibrotic potential by targeting PDGFRB in HSCs.
- In vivo studies utilized mouse models (BDL and TAA) and AAV-mediated gene delivery for therapeutic evaluation.
Main Results:
- miR-149-5p, enriched in hepatocyte exosomes, inhibits HSC activation and collagen deposition by targeting PDGFRB.
- During fibrosis, PU.1 suppresses miR-149-5p transcription in hepatocytes, reducing exosomal delivery and promoting HSC activation.
- Therapeutic administration of miR-149-5p (via AAV or agomir) significantly reduced liver fibrosis in mouse models.
Conclusions:
- The PU.1-miR-149-5p-PDGFRB axis is a critical regulator of liver fibrosis progression.
- Targeting this axis, particularly with miR-149-5p agomir, presents a promising therapeutic strategy for liver fibrosis.
