Stat3 Regulates Liver Progenitor Cell-Driven Liver Regeneration in Zebrafish

Area of Science:

• Hepatology
• Regenerative Medicine
• Molecular Biology

Background:

• Liver injury can trigger regeneration via hepatocyte proliferation or, if compromised, through biliary epithelial cells (BECs) dedifferentiating into liver progenitor cells (LPCs).
• Signal transducer and activator of transcription 3 (Stat3) and its regulator socs3a are upregulated following hepatocyte ablation in zebrafish models.

Purpose of the Study:

• To investigate the role of the Stat3 pathway in LPC-driven liver regeneration after severe liver injury.

Main Methods:

• Pharmacogenetic ablation of hepatocytes in Tg(fabp10a:CFP-NTR) zebrafish.
• Inhibition of Stat3 using chemical inhibitors (JSI-124, S3I-201) and stat3 zebrafish mutants.
• Analysis of BEC dedifferentiation, LPC differentiation, and cell proliferation.

Main Results:

• Stat3 suppression reduced regenerating liver size and LPC proliferation but did not affect BEC dedifferentiation.
• Stat3 inhibition delayed LPC-to-hepatocyte differentiation and decreased BEC numbers.
• Stat3 mutants partially phenocopied these effects, and socs3a mutants showed reduced BEC numbers.

Conclusions:

• The Stat3/Socs3a pathway is essential for timely LPC-to-hepatocyte differentiation.
• This pathway is also critical for maintaining adequate BEC numbers during LPC-driven liver regeneration.