Activation and Spatial Redistribution of RNA Splicing Factors Trigger Hepatic Regeneration

Area of Science:

• Hepatology
• Molecular Biology
• Regenerative Medicine

Background:

• Liver failure and hepatic diseases arise from tissue injury with impaired regeneration.
• Precise molecular and spatial changes initiating liver regeneration are not fully understood.

Purpose of the Study:

• To elucidate the key molecular factors and spatial alterations driving liver regeneration.
• To identify therapeutic targets for liver diseases, including metabolic dysfunction-associated steatotic liver disease.

Main Methods:

• Spatiotemporal sequencing of regenerating liver and single-cell RNA sequencing of hepatocyte organoids (Hep-Orgs).
• In vivo validation using knockout mice models to assess splicing factor function.

Main Results:

• Upregulation of splicing factors (SFs) observed in the regenerative zones of the liver and in precycling/cycling hepatocytes within Hep-Orgs.
• Splicing inhibitors suppressed liver regeneration by increasing ribosomal proteins.
• HNRNPU identified as a key SF crucial for liver regeneration and preventing chronic liver diseases.

Conclusions:

• Spatial remodeling of upregulated RNA SFs initiates the regenerative wave from the periportal zone.
• Highly expressed SFs define repopulating hepatocyte subpopulations.
• Inhibition of RNA splicing leads to ribosomal protein upregulation, reduced proliferation, and lipid accumulation, while SF knockout causes regeneration failure and zonal disruption. SF reduction is a biomarker for severe metabolic dysfunction-associated steatotic liver disease.