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Review
. 2022 May 31;11(11):1809.
doi: 10.3390/cells11111809.

Targeting the Subventricular Zone to Promote Myelin Repair in the Aging Brain

Arthur Morgan Butt  1 , Andrea Dominico Rivera  1   2 , Daniel Fulton  3 , Kasum Azim  4
Affiliations
Review

Targeting the Subventricular Zone to Promote Myelin Repair in the Aging Brain

Arthur Morgan Butt et al. Cells. .

Abstract

The subventricular zone (SVZ) is the largest and most active germinal zone in the adult forebrain. Neural stem cells (NSCs) of the SVZ generate olfactory interneurons throughout life and retain the intrinsic ability to generate oligodendrocytes (OLs), the myelinating cells of the central nervous system. OLs and myelin are targets in demyelinating diseases such as multiple sclerosis (MS). Remyelination is dependent on the ability of oligodendrocyte progenitor cells (OPCs) to proliferate, migrate, and terminally differentiate into myelinating OLs. During aging, there is a gradual decrease in the regenerative capacity of OPCs, and the consequent loss of OLs and myelin is a contributing factor in cognitive decline and the failure of remyelination in MS and other pathologies with aging contexts, including Alzheimer's disease (AD) and stroke. The age-related decrease in oligodendrogenesis has not been fully characterised but is known to reflect changes in intrinsic and environmental factors affecting the ability of OPCs to respond to pro-differentiation stimuli. Notably, SVZ-derived OPCs are an important source of remyelinating OLs in addition to parenchymal OPCs. In this mini-review, we briefly discuss differences between SVZ-derived and parenchymal OPCs in their responses to demyelination and highlight challenges associated with their study in vivo and how they can be targeted for regenerative therapies in the aged brain.

Keywords: aging; multiple sclerosis; oligodendrogenesis; remyelination; subventricular zone.

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Conflict of interest statement

The authors declare no competing or financial interests.

Figures

Figure 1
Figure 1
Forebrain oligodendrogenesis and remyelination efficiencies in young versus aged adults. (A) Coronal brain section counterstained for nuclei; the corpus callosum is evident as light grey, and the SVZ zones and other regions of interest are indicated. The dorsoventral gradient of oligodendrogenesis in the SVZ is illustrated; OPCs are generated primarily from NSCs in the dorsal microdomain, and at lower rates in the most ventral regions of the SVZ. This preferential generation of OLs from the dorsal SVZ persists in adulthood and is increased following demyelination. (B) During postnatal development, the majority of OLs in the dorsal forebrain are derived from NSC located in the dorsal SVZ that progress through a number of distinct differentiation stages in response to intrinsic and extrinsic cues (see (E) for explanations of pictograms of the differentiation stages): quiescent NSCs have small nuclei and in response to appropriate stimuli can transform into activated NSCs that have larger nuclei; activated NSCs generate transiently amplifying progenitors (TAPs), which is a pre-OPC stage that gives rise to migratory and proliferative OPCs with a simple processing-bearing morphology; OPCs migrate to their final sites, where they undergo self-replication and generate newly formed (NF)OLs, which have a complex process-bearing morphology and are non-proliferative; NFOLs differentiate into mature myelinating (M)OLs; slowly proliferating parenchymal OPCs with a highly complex ramified morphology persist after the main developmental period of myelination. (C) In young adults, demyelinating insults trigger efficient remyelination by parenchymal OPCs that are located at or near to the lesion site. Additionally, morphologically simpler and highly migratory OPCs are recruited from dorsal NSCs of the SVZ to replenish parenchymal OPCs and contribute to remyelination. (D) The aged brain is characterised by inefficient regeneration of MOLs both from parenchymal and SVZ-derived OPCs, resulting in impaired remyelination; in the aged SVZ, dorsal NSCs are able to regenerate NFOLs, but these fail to progress into remyelinating MOLs, suggesting a deficiency of appropriate extrinsic stimuli (indicated by ‘?’). (E) Identifying the transcriptional networks that regulate each stage of oligodendrogenesis from dorsal NSCs will enable the development of targeted therapies that rejuvenate aged NSCs and stimulate replenishment of OPCs to promote remyelination and repair in the aged brain. Abbreviations: NSC = neural stem cell; TAPs = transiently amplifying progenitors (pre-OPC stage); OPC = oligodendrocyte precursor cell; NFOL = non-myelin forming oligodendrocyte; MOL = mature oligodendrocyte.
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