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

After severe liver injury, biliary epithelial cells (BECs) dedifferentiate into bipotential progenitor cells (BPPCs), which subsequently redifferentiate into nascent hepatocytes to support liver regeneration. However, the mechanisms governing BPPCs redifferentiation, 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 redifferentiation 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.