RESUMO
The scarcity of tissue-specific stem cells and the complexity of their surrounding environment have made molecular characterization of these cells particularly challenging. Through single-cell transcriptome and weighted gene co-expression network analysis (WGCNA), we uncovered molecular properties of CD133(+)/GFAP(-) ependymal (E) cells in the adult mouse forebrain neurogenic zone. Surprisingly, prominent hub genes of the gene network unique to ependymal CD133(+)/GFAP(-) quiescent cells were enriched for immune-responsive genes, as well as genes encoding receptors for angiogenic factors. Administration of vascular endothelial growth factor (VEGF) activated CD133(+) ependymal neural stem cells (NSCs), lining not only the lateral but also the fourth ventricles and, together with basic fibroblast growth factor (bFGF), elicited subsequent neural lineage differentiation and migration. This study revealed the existence of dormant ependymal NSCs throughout the ventricular surface of the CNS, as well as signals abundant after injury for their activation.
Assuntos
Epêndima/citologia , Células-Tronco Neurais/metabolismo , Antígeno AC133 , Animais , Antígenos CD/metabolismo , Diferenciação Celular , Movimento Celular , Epêndima/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Glicoproteínas/metabolismo , Camundongos , Células-Tronco Neurais/citologia , Peptídeos/metabolismo , Análise de Sequência de RNA , Análise de Célula Única , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Oligodendrogliopathy, microglial infiltration, and lack of remyelination are detected in the brains of patients with multiple sclerosis and are accompanied by high levels of the transcription factor p53. In this study, we used the cuprizone model of demyelination, characterized by oligodendrogliopathy and microglial infiltration, to define the effect of p53 inhibition. Myelin preservation, decreased microglial recruitment, and gene expression were observed in mice lacking p53 or receiving systemic administration of the p53 inhibitor pifithrin-alpha, compared with untreated controls. Decreased levels of lypopolysaccharide-induced gene expression were also observed in vitro, in p53(-/-) primary microglial cultures or in pifithrin-alpha-treated microglial BV2 cells. An additional beneficial effect of lack or inhibition of p53 was observed in Sox2+ multipotential progenitors of the subventricular zone that responded with increased proliferation and oligodendrogliogenesis. Based on these results, we propose transient inhibition of p53 as a potential therapeutic target for demyelinating conditions primarily characterized by oligodendrogliopathy.