RESUMO
A lack of sufficient oligodendrocyte myelination contributes to remyelination failure in demyelinating disorders. miRNAs have been implicated in oligodendrogenesis; however, their functions in myelin regeneration remained elusive. Through developmentally regulated targeted mutagenesis, we demonstrate that miR-219 alleles are critical for CNS myelination and remyelination after injury. Further deletion of miR-338 exacerbates the miR-219 mutant hypomyelination phenotype. Conversely, miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice. Integrated transcriptome profiling and biotin-affinity miRNA pull-down approaches reveal stage-specific miR-219 targets in oligodendrocytes and further uncover a novel network for miR-219 targeting of differentiation inhibitors including Lingo1 and Etv5. Inhibition of Lingo1 and Etv5 partially rescues differentiation defects of miR-219-deficient oligodendrocyte precursors. Furthermore, miR-219 mimics enhance myelin restoration following lysolecithin-induced demyelination as well as experimental autoimmune encephalomyelitis, principal animal models of multiple sclerosis. Together, our findings identify context-specific miRNA-regulated checkpoints that control myelinogenesis and a therapeutic role for miR-219 in CNS myelin repair.
Assuntos
Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , MicroRNAs/metabolismo , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Regeneração Nervosa , Cicatrização , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Deleção de Genes , Lecitinas/farmacologia , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Esclerose Múltipla/terapia , Bainha de Mielina/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/genética , Proteínas do Tecido Nervoso/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Nervo Óptico/patologia , Nervo Óptico/ultraestrutura , Fenótipo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Cicatrização/efeitos dos fármacos , Cicatrização/genéticaRESUMO
It has been proved that Uygur herb Hyssopus offcinalis L. could affect the levels of some cytokines (such as IL-4, IL-6, IL-17, and IFN-γ) in asthmatic mice. By detection of the expressions of MMP-9 and TIMP-1 and the morphological changes, the aim of this research is to reveal the mechanism of Uygur herb Hyssopus offcinalis L. in the process of airway remodeling. It was observed that the expressions of MMP-9 and TIMP-1 increased, but the ratio of MMP-9/TIMP-1 decreased in airway remodeling group. However, the expression of both MMP-9 and TIMP-1 decreased after being treated with dexamethasone and Hyssopus offcinalis L., accompanied by the relieved pathological changes, including collagen deposition, mucus secretion, and smooth muscle proliferation. It is suggested that Uygur herb Hyssopus offcinalis L. could inhibit airway remodeling by correcting imbalance of MMP-9/TIMP-1 ratio.