Regulating The Immune Micro-environment To Promote The Transplantation Of Stem Cells And Functional Recovery Of Neural System

Background and objectiveSpinal cord injury(SCI)is a severe neurological traumatic condition that results in sensory and motor deficits.SCI imposes significant burdens on the health care system as well as the patients and their caregivers.Despite recent advances in medical care,efficient treatment options are still limited.Among the experimental treatment options,neural stem cells(NSCs)are a promising therapeutic strategy.The therapeutic mechanisms includes functional remyelination,neurotrophic factors secretion and immunomodulation effects,however,the inability of transplanted NSCs to replace neuronal loss through successful differentiation is a major obstacle for wide application.Therefore,a better understanding of SCI pathophysiology could help in optimizing therapeutic strategies that involve NSC transplantation.Methods and ResultsFirstly,we used immunofluorescent staining and qRT-PCR methods to detect infiltrated immune cells and secreted cytokines at different time points after SCI.It was found that a large number of macrophages continuously accumulated the lesion site and presented a M2 to M1 phenotypic transition.At the molecular lever,IL-6,IL-1? and TNF-? were the most changeable cytokines.We examined the effects of immune cells and molecules on NSCs in vitro.Different dose IL-6 was added into the NSCs culture medium,which was found to promote proliferation and differentiation into astrocytes.We also generated the co-culture system between polarized macrophages and NSCs,found macrophages could induce the death of NSCs during their differentiation process,and this effect was mediated by the cytokines IL-1? and TNF-?.We used two strategies to treat SCI in vivo.One strategy was repeatedly administering clodronate-liposomes via intravenous injection to long-term eliminate the peripheral macrophages;the other was local usage of IFN-?antibody to impede macrophage polarizing to M1 phenotype.Both strategies significantly promoted the functional recovery in mice after SCI.ConclusionMacrophages were predominant immune cells after SCI and could induce the death of NSCs during their differentiation process.IL-6,IL-1? and TNF-? were the most changeable cytokines after SCI.IL-6 promoted the proliferation and differentiation into astrocytes of NSCs;while IL-1? and TNF-?were participated in the NSCs' death induced process of macrophages.After SCI,long-term depletion of peripheral macrophages and blocking the phenotypic transition process of macrophages both promoted the functional recovery significantly.