The Roles And Mechanisms Of Oligodendrocyte Precursor Cell Transplantation And Fingolimod Treatment After Cerebral Ischemia In Mice

The proliferation,migration and differentiation of endogenous oligodendrocyte precursor cell(OPC)are limited after ischemic stroke,resulting in the insufficient repair of injured white matter and damaged axons,which are related to the long-term neurological deficits.Exogenous OPCs provide an opportunity to differentiate into oligodendrocytes after their transplantation.A large number of studies on demyelinating diseases have shown that transplanted OPC was capable of participating in remyelination.Drugs or growth factors are also promising strategies to enhance the oligodendrogenesis after cerebral ischemia.Fingolimod is a drug that has been approved for the treatment of multiple sclerosis.It has been demonstrated that fingolimod promoted the proliferation and differentiation of OPC in animal models of multiple sclerosis.This study aims to explore the effects and mechanisms of OPC transplantation and fingolimod treatment on myelin regeneration and other processes after ischemic stroke in mice.Recently,the study from our group demonstrated that transplanting OPC in the acute phase of ischemic stroke protected the blood-brain barrier integrity.However,the effect of transplanting OPC during the recovery phase of ischemic stroke and its potential role on oligodendrogenesis and long-term functional recovery still need to be further investigated.A mouse cerebral ischemia model was built by transient middle cerebral artery occlusion(t MCAO),and OPC was transplanted to the perifocal area at7 days after ischemia.By tracking the transplanted OPC cells,I observed that the survival and differentiation of OPC in the brain after four weeks of transplantation were very limited.Therefore,I hypothesized the transplanted OPC might influence the brain microenvironment through paracrine mechanisms.The results revealed that OPC transplantation during the recovery phase reduced the brain atrophy volume and improved the neurological function recovery of mice.In addition,the transplanted OPC enhanced the proliferation and migration of endogenous oligodendrocytes,which was associated with the upregulation of the chemokine ligand 12(C-X-C motif chemokine ligand 12,CXCL12)in endothelial cells.In vitro co-culture experiments using OPCs and neurons confirmed that OPC promoted the neurite growth and synaptogenesis via secreting netrin-1 and acted through the deleted in colorectal carcinoma(DCC)receptor on neurons.It has been reported that acute treatment with fingolimod after ischemic stroke improved recovery in mice with normal glucose levels.But the correlation of fingolimod treatment time and efficacy in diabetic stroke mice is not clear.In this study,the results of fingolimod treatment of diabetic mice after cerebral ischemia at different time points showed that interventions in the acute and recovery phases had different effects on mice.Administration of fingolimod at 24 hours after t MCAO successfully reduced the infiltration of MPO-positive inflammatory cells and inhibited the expression of TNF-α and cell apoptosis.However,fingolimod treatment in the acute phase significantly aggravated the brain edema and the leakage of blood-brain barrier,offsetting its beneficial anti-inflammatory and anti-apoptotic effects,resulting in a poor prognosis in mice.On the contrary,fingolimod treatment at 7 to 14 days after t MCAO increased blood vessel density,enhanced angiogenesis and neurogenesis,as well as protected the white matter integrity.In conclusion,this study investigated the roles and mechanisms of OPC transplantation and fingolimod treatment in mice with ischemic stroke.The results suggested that both OPC transplantation and fingolimod intervention during the recovery phase can serve as potential treatment methods for the cerebral ischemia,extending the time window of ischemic stroke therapy.