Mechanisms of oligodendrocyte regeneration from ventricular-subventricular zone-derived progenitor cells in white matter diseases

Abstract

White matter dysfunction is an important part of many CNS disorders including multiple sclerosis (MS) and vascular dementia. Within injured areas, myelin loss and oligodendrocyte death may trigger endogenous attempts at regeneration. However, during disease progression, remyelination failure may eventually occur due to impaired survival/proliferation, migration/recruitment, and differentiation of oligodendrocyte precursor cells (OPCs). The ventricular-subventricular zone (V-SVZ) and the subgranular zone (SGZ) are the main sources of neural stem/progenitor cells (NSPCs), which can give rise to neurons as well as OPCs. Under normal conditions in the adult brain, the V-SVZ progenitors generate a large number of neurons with a small number of oligodendrocyte lineage cells. However, after demyelination, the fate of V-SVZ-derived progenitor cells shifts from neurons to OPCs, and these newly generated OPCs migrate to the demyelinating lesions to ease white matter damage. In this mini-review, we will summarize the recent studies on extrinsic (e.g., vasculature, extracellular matrix (ECM), cerebrospinal fluid (CSF)) and intrinsic (e.g., transcription factors, epigenetic modifiers) factors, which mediate oligodendrocyte generation from the V-SVZ progenitor cells. A deeper understanding of the mechanisms that regulate the fate of V-SVZ progenitor cells may lead to new therapeutic approaches for ameliorating white matter dysfunction and damage in CNS disorders.

Keywords: demyelination; multiple sclerosis; neural stem/progenitor cells; oligodendrocyte precursor cells; oligodendrogenesis; subventricular zone; vascular dementia.

Figure 1

Schematic of fate of neuronal, astroglial, oligodendrocytic lineage cells in V-SVZ. (A) Type B cells retain neuroepithelial trait and function as NSPCs in the V-SVZ. Type B cells slowly divide and give rise to rapidly dividing type C cells (IPCs), which generate neuroblasts (type A cells). The type B cells can also generate astrocytes and Olig2-expressing type C cells. The Olig2-expressing type C cells give rise to highly migratory OPCs, which differentiate into myelinating oligodendrocytes. (B) Neurons, astrocytes, and oligodendrocytes, derived from V-SVZ NSPCs (type B cells), interact with each other to maintain proper neural function. Red: neuron, green: astrocyte, blue: oligodendrocyte.

Figure 2

Schematic of interplay for SVZ cells. The subventricular zone (SVZ) and ventricular zone (VZ) are lining the lateral ventricles (V) in the brain. Type B cells (B) contact the ventricle (V) containing CSF through specialized apical processes. The processes contain a single primary cilium, which is surrounded by a rosette of ependymal cells (E) with large apical surfaces forming pinwheel-like structures. On the other side, the type B cells have long basal processes with specialized endings that frequently contact BV. The type B cells also contact their progeny, i.e., type C cells (C) and the chains of migrating type A neuroblasts (A). The V-SVZ includes ECM (fractones) that contacts all the cell types including BV, microglia, and astrocytes in this region.

Figure 3

Schematic of behavior of NSPCs and OPCs after demyelination. In response to myelin loss or oligodendrocyte death, both NSPCs and OPCs would attempt to repair the white matter damage by proliferating, migrating to the injured areas, and restoring myelinating oligodendrocytes. If the damaged area is restricted in the corpus callosum (2), V-SVZ-derived NSPCs would shift from neuronal lineage cells to oligodendroglial lineage cells. In addition, residing OPCs adjacent to the damaged area may also contribute to the repairing. Although the V-SVZ-derived NSPCs could travel to the cortex (1) or striatum (3), the recruitment of local OPCs/NSPCs outside of the V-SVZ (e.g., pia matter and/or cortical layer 1) to the lesion area would be more important when the demyelination occur in these areas.