The Role Of MicroRNAs In Modulating Neural Stem Cell Proliferation And Differentiation

Neural stem cells(NSCs)are a class of multipotent stem cells that possess unlimited abilities to self-renew and proliferation but whose progeny are restricted to neural lineages.They can generate three major central nervous system cell types:neurons,astrocytes and oligodendrocytes.However,the molecular mechanisms that regulate NSCs fate determination are not yet fully understoodMicroRNAs are a class of small non-coding single-stranded RNA with a length of about 22 nucleotides.They can regulate the genes expression at the post-transcriptional level by binding to mRNA 3'end untranslated region.In mammals,the developing brain contains a large,diverse group of miRNAs,which suggests that miRNAs may play very crucial roles in neural stem cell fate determination and the development of the central nervous system.In the first section,we analyzed the miRNAs expression pattern in the mouse cerebral cortex during various developmental stages.Among those miRNAs,miR-17 family miRNAs were highly expressed and that their expression levels gradually reduced as the cortex developed.Furthermore,miR-17-5p,with the highest expression level among the miR-17 family,in which the change occurred in the ventricular zone/sub-ventricular zone.In addition to inducing the proliferation of neural stem cells,miR-17-5p also promotes neurogenesis and inhibits astrocytogenesis.Besides,we confirm that these effects of miR-17-5p were mainly the result of its inhibition of BMP signaling pathway by targeting BMPR2.In the second section,we focus on the study of neural stem cell transplantation involving miRNAs as a promising strategy for nervous system diseases and brain injury.A mass of researches verify that the low yield of NSCs-derived neurons hinders their potential for neural replacement.Circumstantial evidence suggests that neuroinflammation is always aroused during the process of nervous system diseases or brain injury,even after cell replacement.The inflammation environment gives the rise to the activation of endogenous glial cells that release inflammatory cytokines,such as leukemia inhibitory factor(LIF)and ciliary neurotrophic factor(CNTF),that further induce astrocytogenesis,thus bating neuronal differentiation from NSCs.We found that miR-17-92 cluster might suppress the LIF,CNTF signaling by targeting multiple key proteins related to JAK/STAT pathway.Both in vitro and in vivo studies indicate that overexpression of miR-17-92 cluster can increase the ratio of neuronal differentiation and improve cell replacement effect by repressing JAK/STAT signaling pathway.Taken together,we not only demonstrate miR-17 family members modulate the proliferation and differentiation of NSCs in the development of mouse cortex that suggests miR-17 family may play a vital role in the development of central nervous system.Meanwhile,we also testify that overexpression of miR-17-92 cluster in NSCs may encourage neurogenesis of grafted cells,thus improving treatment effect.Our project not only helps to elucidate the mechanism of miRNAs involved in the regulation of nervous system development,but also provides us with new venues for cell replacement therapy for nervous system disease and brain lesion.