Khdrbs1 drives re-differentiation of bipotential progenitor cells by inhibiting p53 in zebrafish biliary-mediated liver regeneration

After severe liver injury, biliary epithelial cells (BECs) undergo de-differentiation into bipotential progenitor cells (BPPCs), which subsequently re-differentiate into nascent hepatocytes and BECs to accomplish liver regeneration. However, the crucial factors governing the re-differentiation process of BPPCs remain largely unknown. Here, using a zebrafish model of severe liver injury, we observed specific expression of khdrbs1a and khdrbs1b (collectively known as khdrbs1) in BPPCs through single-cell RNA analyses and fluorescence in situ hybridization. Subsequently, to eliminate the genetic compensation, we generated a CRISPR/dead Cas9-mediated system for interfering with khdrbs1 in BECs, which caused defective liver regeneration and impaired re-differentiation of BPPCs. Furthermore, the khdrbs1-/- mutant displayed impaired proliferation and re-differentiation of BPPCs during liver regeneration. Mechanistically, p53 signaling was activated in response to the loss of khdrbs1, and tp53 mutation partially rescued the defective liver regeneration of the khdrbs1-/- mutant. In summary, we conclude that Khdrbs1 promotes the re-differentiation of BPPCs in part by inhibiting p53 activation during biliary-mediated liver regeneration in zebrafish.