RESUMEN
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.
Asunto(s)
Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , MicroARNs/metabolismo , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , Regeneración Nerviosa , Cicatrización de Heridas , Animales , Diferenciación Celular/efectos de los fármacos , Linaje de la Célula/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Eliminación de Gen , Lecitinas/farmacología , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Esclerosis Múltiple/terapia , Vaina de Mielina/efectos de los fármacos , Regeneración Nerviosa/efectos de los fármacos , Regeneración Nerviosa/genética , Proteínas del Tejido Nervioso/metabolismo , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Nervio Óptico/patología , Nervio Óptico/ultraestructura , Fenotipo , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Médula Espinal/patología , Cicatrización de Heridas/efectos de los fármacos , Cicatrización de Heridas/genéticaRESUMEN
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.