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 (PrPC) genes in rat adipose-derived mesenchymal stromal cells (ADMSCs) (ie, MSCDGe-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 MSCDGe-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-MSCOVE-PrPC), 4 (IR-MSCOVE- ZNF746), and 5 (IR-MSCDGe-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, MSCDGe-OVEenhanced cell proliferation and growth and ameliorated IR-induced liver damage.