Downregulation of Augmenter of Liver Regeneration Impairs the Therapeutic Efficacy of Liver Epithelial Progenitor Cells Against Acute Liver Injury by Enhancing Mitochondrial Fission

Abstract

Cell-based therapeutic approaches have been proven to be effective strategies for the treatment of acute liver injury (ALI). However, widespread application of these procedures is limited by several key issues, including rapid loss of stemness in vitro, aberrant differentiation into undesirable cell types, and low engraftment in vivo. In this study, liver epithelial progenitor cells (LEPCs) were characterized and transfected with augmenter of liver regeneration (ALR). The results revealed that in ALI mice with CCl₄, the transplantation of ALR-bearing LEPCs into the liver markedly protected mice against ALI by decreasing the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), thus relieving hepatic tissue injury and attenuating inflammatory infiltration. Mechanistically, the knockdown of ALR in LEPCs activated the phosphorylation of dynamin-related protein 1 (Drp1) at the S616 site and thereby enhanced mitochondrial fission. In contrast, the transfection of ALR into LEPCs significantly inhibited Drp1 phosphorylation, thereby favoring the maintenance of mitochondrial integrity and the preservation of adenosine triphosphate contents in LEPCs. Consequently, the ALR-bearing LEPCs transplanted into ALI mice exhibited substantially greater homing ability to the injured liver via the SDF-1/CXCR4 axis than that of LEPCs-lacking ALR. In conclusion, we demonstrated that the transplantation of ALR-transfected LEPCs protected mice against CCl₄-induced ALI, thus offering immense curative potential in the clinic.

Knockdown of augmenter of liver regeneration (ALR) in liver epithelial progenitor cells (LEPCs) impaired cell survival and resulted in excessive mitochondrial fission partially by activation of dynamin-related protein 1 (Drp1) phosphorylation at S616. Overexpression of ALR in LEPCs significantly inhibited Drp1 phosphorylation, maintained the mitochondrial integrity and the preservation of adenosine triphosphate contents. Consequently, the ALR-bearing LEPCs transplanted into ALI mice exhibited substantially greater homing ability to the injured liver through SDF-1/CXCR4 axis than that of LEPCs-lacking ALR.

acute liver injury, augmenter of liver regeneration, cell transplantation, dynamin-related protein 1, liver epithelial progenitor cells