PDGF signaling drives bipotential progenitor cell re-differentiation during zebrafish biliary-mediated liver regeneration

After severe liver injury, biliary epithelial cells (BECs) de-differentiate into bipotential progenitor cells (BPPCs), which subsequently re-differentiate into nascent hepatocytes to support liver regeneration. However, the mechanisms governing BPPCs re-differentiation, particularly the role of non-parenchymal cells, remain poorly understood. Here, using a zebrafish model of extreme hepatocyte ablation, we demonstrate that platelet-derived growth factor (PDGF) ligands are rapidly induced in BPPCs and bind to Pdgfra on neighboring hepatic stellate cells (HSCs). Genetic inactivation or dominant-negative inhibition of pdgfra impairs HSC expansion and reduces HSC-derived midkine a (Mdka) expression, thereby limiting the re-differentiation of BPPCs into hepatocytes. Notably, heat-shock-induced mdka overexpression partially rescues the regenerative defect. Together, our findings identify a BPPC-HSC paracrine feedback loop mediated by the PDGF-Pdgfra-Mdka axis that is essential for biliary-mediated liver regeneration. Targeting this axis may provide a therapeutic strategy for end-stage liver diseases.