The Anti-inflammatory Effect Of Neural Stem Cell Transplantation In Intracerebral Hemorrhage Model And Its Possible Mechanism

Background and Objective:Intracerebral hemorrhage(ICH)is a subtype of stroke,counting for 10-15% of all strokers.ICH bring great impact and heavy economic burden to the family and society,with high morbidity and mortality.The inflammatory response is closely related to brain edema,blood brain barrier(BBB)breakdown and disease deterioration following ICH.A large number of animal studies have shown that neural stem cells(NSCs)transplantation is a promising strategy for ICH therapy.The transplanted NSCs can play a protective role in ICH,such as anti-inflammation,anti-apoptosis and promoting angiogenesis.However,the specific mechanism of alleviating inflammation is unclear.Therefore,this study aim to investigate the antiinflammatory effects of NSCs following ICH both in vivo and in vitro and then explore the possible mechanism at the signaling pathway transduction level.Methods:1.Construct ICH model by collagenase injection into the brain;and then transplant NSCs via tail vein injection 2h after ICH model induction;observe the effect of NSCs on inflammation,MAPKs(ERK1/2,p38 and JNK)singling pathways,brain edema,BBB and behavioral test at day 3 post ICH.2.Stimulate macrophage with 10% hemolysate to copy the inflammatory response following ICH in vitro;then study the activation and role of ERK1/2,p38 and JNK signaling pathways in hemolysate induced macrophage by the application of their inhibitors;co-culture NSCs with macrophage to investigate the anti-inflammatory effect and its possible mechanism of NSCs in vitro in the treatment of hemorrhagic disease.Results:1.The ICH model was successfully constructed by stereotaxic injection collagenase into left striate;the transplanted NSCs can reached the peri-hematoma region via tail vein injection;at day 3 after ICH,there happened severe inflammatory response around the hematoma,such as the activation of microglia/macrophage,the up-regulation of inflammatory mediators(COX-2,IL-1? and TNF-α)and the activation of MAPKs(ERK1/2,p38 and JNK)signaling pathway;the transplantation of NSCs can alleviate the activation of microglia/macrophage,down-regulate the level of inflammatory mediators and activation of MAPKs signaling pathway,reduce the brain edema and BBB breakdown,as well as promote the functional recovery.2.The macrophage become large in body,extend many bumps at the surface and secret more inflammatory mediators(COX-2,IL-1? and TNF-α)in response to hemolysate,suggesting the model can successfully copy the inflammatory response after ICH;the MAPKs(ERK1/2,p38 and JNK)signaling pathway were triggered quickly and participated in the regulation of inflammatory response in hemolysate induced macrophage;NSCs can reduce the level of the above three kinds of inflammatory mediators and suppress the activation of MAPKs signaling pathway in co-culture system.Conclusion:This study showed that early NSCs transplantation can reduce the inflammatory response,reduce brain edema and BBB damage as well as promote the functional recovery at day 3 post-ICH,and its anti-inflammatory effects may be mediated by suppressing ERK1/2,p38 and JNK pathway in macrophage.