GRP78 improves the therapeutic effect of mesenchymal stem cells on hemorrhagic shock‐induced liver injury: Involvement of the NF–кB and HO‐1/Nrf‐2 pathways

Mesenchymal stem cells (MSCs) are a popular cell source for repairing the liver. Improving the survival rate and colonization time of MSCs may significantly improve the therapeutic outcomes of MSCs. Studies showed that 78‐kDa glucose‐regulated protein (GRP78) expression improves cell viability and migration. This study aims to examine whether GRP78 overexpression improves the efficacy of rat bone marrow‐derived MSCs (rBMSCs) in HS‐induced liver damage. Bone marrow was isolated from the femurs and tibias of rats. rBMSCs were transfected with a GFP‐labeled GRP78 expression vector. Flow cytometry, transwell invasion assay, scratch assay immunoblotting, TUNEL assay, MTT assay, and ELISA were carried out. The results showed that GRP78 overexpression enhanced the migration and invasion of rBMSCs. Moreover, GRP78‐overexpressing rBMSCs relieved liver damage, repressed liver oxidative stress, and inhibited apoptosis. We found that overexpression of GRP78 in rBMSCs inhibited activation of the NLRP3 inflammasome, significantly decreased the levels of inflammatory factors, and decreased the expression of CD68. Notably, GRP78 overexpression activated the Nrf‐2/HO‐1 pathway and inhibited the NF–κB pathway. High expression of GRP78 efficiently enhanced the effect of rBMSC therapy. GRP78 may be a potential target to improve the therapeutic efficacy of BMSCs. Graphical summary of the possible mechanisms of GRP78 overexpression suppressed inflammation, improved antioxidant capacity, and alleviated liver injury caused by HS. Arrow: promotion; “tee” head: inhibition.