Double gene overexpression of ZNF746 and cellular prion protein in rat adipose-derived mesenchymal stromal cell therapy protects the liver against ischemia‒reperfusion injury

This study presents an examination of whether the double overexpression of ZNF746 and cellular prion protein (PrP C ) genes in rat adipose-derived mesenchymal stromal cells (ADMSCs) (ie, MSC DGe-OVE ) offered enhanced protection to the livers of rats against ischemia‒reperfusion (IR) injury. The in vitro results revealed that compared with those of rat ADMSCs, cell activities (viability/proliferation/growth/cell cycle process) were significantly upregulated by the overexpression of either gene in rat ADMSCs and were further significantly increased by MSC DGe-OVE , whereas the expression of biomarkers of oxidative stress/ROS/apoptosis/fibrosis/autophagy decreased with increasing cell viability among the groups (all P < 0.001). Male adult SD rats (n = 50) were equally categorized into groups 1 (sham-operated-control), 2 (IR), 3 (IR-MSC OVE-PrPC ), 4 (IR-MSC OVE- ZNF746 ), and 5 (IR-MSC DGe-OVE ), and livers were harvested by day 3. By day 3, the number of circulatory inflammatory/immune cells, protein expression of oxidative stress/apoptotic/fibrotic/mitochondrial damage/autophagic biomarkers, and cellular levels of DNA damage/fibrosis/inflammation in the liver parenchyma were lowest in group 1, highest in group 2 and significantly lower in groups 3/4 than in group 5 (all P < 0.0001). Liver fibrosis detected by ultrasound and the liver injury score displayed identical patterns of circulatory levels of immune cells among the groups (all P < 0.0001). Upstream and downstream inflammatory and cell-stress signaling pathways were identified as playing crucial roles in acute liver IR injury. In conclusion, MSC DGe-OVE enhanced cell proliferation and growth and ameliorated IR-induced liver damage.