Resolving the transcriptional transitions associated with oligodendrocyte generation from adult neural stem cells by single cell sequencing
AbstractThe subventricular zone (SVZ) is the largest neurogenic niche in the adult forebrain. Notably, neural stem cells (NSCs) of the SVZ generate not only neurons, but also oligodendrocytes, the myelin-forming cells of the central nervous system. Transcriptomic studies have provided detailed knowledge of the molecular events that regulate neurogenesis, but little is understood about adult oligodendrogenesis from SVZ-NSCs. To address this, we performed in-depth single-cell transcriptomic analyses to resolve the major differences in neuronal and oligodendroglial lineages derived from the adult SVZ. A hallmark of adult oligodendrogenesis was the stage-specific expression of transcriptional m…
Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity
Strategies for promoting neural regeneration are hindered by the difficulty of manipulating desired neural fates in the brain without complex genetic methods. The subventricular zone (SVZ) is the largest germinal zone of the forebrain and is responsible for the lifelong generation of interneuron subtypes and oligodendrocytes. Here, we have performed a bioinformatics analysis of the transcriptome of dorsal and lateral SVZ in early postnatal mice, including neural stem cells (NSCs) and their immediate progenies, which generate distinct neural lineages. We identified multiple signaling pathways that trigger distinct downstream transcriptional networks to regulate the diversity of neural cells …
Taking Advantage of Nature’s Gift: Can Endogenous Neural Stem Cells Improve Myelin Regeneration?
Irreversible functional deficits in multiple sclerosis (MS) are directly correlated to axonal damage and loss. Neurodegeneration results from immune-mediated destruction of myelin sheaths and subsequent axonal demyelination. Importantly, oligodendrocytes, the myelinating glial cells of the central nervous system, can be replaced to some extent to generate new myelin sheaths. This endogenous regeneration capacity has so far mainly been attributed to the activation and recruitment of resident oligodendroglial precursor cells. As this self-repair process is limited and increasingly fails while MS progresses, much interest has evolved regarding the development of remyelination-promoting strateg…
Drug connectivity mapping and functional analysis reveals therapeutic small molecules that differentially modulate myelination
AbstractOligodendrocytes are the myelin forming cells of the central nervous system (CNS) and are generated from oligodendrocyte progenitor cells (OPCs). Disruption or loss of oligodendrocytes and myelin has devastating effects on CNS function and integrity, which occurs in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer’s disease (AD) and neuropsychiatric disorders. Hence, there is a need to develop new therapies that promote oligodendrocyte regeneration and myelin repair. A promising approach is drug repurposing, but most agents have potentially contrasting biological actions depending on the cellular context and their dose-dependent effects on intracellular r…
Drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination
Disruption or loss of oligodendrocytes (OLs) and myelin has devastating effects on CNS function and integrity, which occur in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer’s disease and neuropsychiatric disorders. Hence, there is a need to develop new therapies that promote oligodendrocyte regeneration and myelin repair. A promising approach is drug repurposing, but most agents have potentially contrasting biological actions depending on the cellular context and their dose-dependent effects on intracellular pathways. Here, we have used a combined systems biology and neurobiological approach to identify compounds that exert positive and negative effects on olig…