Potential role of NGF, BDNF, and their receptors in oligodendrocytes differentiation from neural stem cell: An in vitro study.

Neural stem cells (NSCs) or neuronal progenitor cells are cells capable of differentiating into oligodendrocytes, myelin-forming cells that have the potential of remyelination. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are two neurotrophic factors that have been studied to stimulate NSC differentiation thus playing a role in multiple sclerosis pathogenesis and several other demyelinating disorders. While several studies have demonstrated the proliferative and protective capabilities of these neurotrophic factors, their cellular and molecular functions are still not well understood. Thus, in the present study, we focus on understanding the role of these neurotrophins (BDNF and NGF) in oligodendrogenesis from NSCs. Both neurotrophic factors have been shown to promote NSC proliferation and NSC differentiation particularly into oligodendroglial lineage in a dose-dependent fashion. Further, to establish the role of these neurotrophins in NSC differentiation, we have employed pharmacological inhibitors for TrkA and TrkB receptors in NSCs. The use of these inhibitors suppressed NSC differentiation into oligodendrocytes along with the downregulation of phosphorylated ERK suggesting active involvement of ERK in the functioning of these neurotrophins. The morphometric analysis also revealed the important role of both neurotrophins in oligodendrocytes development. These findings highlight the importance of neurotrophic factors in stimulating NSC differentiation and may pave a role for future studies to develop neurotrophic factor replacement therapies to achieve remyelination.

Role of astrocytic MeCP2 in regulation of CNS myelination by affecting oligodendrocyte and neuronal physiology and axo-glial interactions.

Astrocytes perform several critical functions such as promoting neuronal maturation, neuronal survival, maintaining and supporting neurons and oligodendrocytes. Astrocytes participate in the formation of nodes of Ranvier. Recently, studies emphasizing on the role of astrocytes in regulating myelination by secreting pro-myelinating factors like growth factors, neurotrophins and ECM proteins, have been investigated by many researchers. Methyl-CpG-Binding Protein 2 (MeCP2), an epigenetic protein, binds to CpG islands in the genome and induces multiple gene regulatory functions by conforming changes in the chromatin structure and resulting in cell-specific gene expression. MeCP2 deficient astrocytes have been linked with abnormal neuronal function including decreased dendritic arborization and decreased dendritic outgrowth. However, role of astrocytic MeCP2 in central nervous system myelination is largely not known. The data from the current study indicate altered mRNA levels (Lif, Cntf, Pdgfa, Cxcl10) of astrocyte-secreted factors involved in myelination. Bdnf and Ngf mRNA levels were also altered in MeCP2 knockdown astrocytes. Moreover, the secreted BDNF levels were significantly altered whereas there were no significant changes in NGF secretion. We also observed that astrocytic MeCP2 affects the morphology, physiology and survival of oligodendrocytes and neurons-two of the key players in myelination. Further, we report that some of the axo-glial interaction genes, namely Caspr, Notch1, Nf155 and Nrg1 are under the regulation of astrocytic MeCP2 along with key myelin genes and proteins.