Can oligodendrocyte precursor cells be a therapeutic target for mitigating cognitive decline in cerebrovascular disease?

Abstract

Oligodendrocyte precursor cells (OPCs) give rise to mature myelin-forming oligodendrocytes during white matter development. In adult brains, some populations of OPCs remain to renew oligodendrocyte pools and myelin. Two recent studies highlight the importance of OPCs in white matter homeostasis. Genetic tracing studies suggest that age-related decline in OPCs may contribute to diminished myelin renewal and memory deficits in mouse models. Single cell transcriptomics and imaging may now define specific subsets of OPCs involved in process elaboration, motility and myelination. These advances raise the possibility of pursuing OPCs as novel therapeutic targets for vascular cognitive impairment.

In the context of an aging society, the prevention of cognitive decline after cerebrovascular disease represents an urgent and unmet need. White matter mechanisms are increasingly recognized to play a central role.¹ In cerebral white matter, axonal bundles sheathed by myelin connect and integrate various cortical areas. For example, the corpus callosum region, which consists of the thickest commissural axonal tract in brain, has millions of myelinated fibers to connect brain hemispheres. In the adult brain, myelination is an important step for learning, and the myelin remodeling comes from the addition of newly generated oligodendrocytes.² Myelinated oligodendrocytes are terminally differentiated and thus do not proliferate. Therefore, oligodendrocyte precursor cells (OPCs) play a critical role in increasing the number of oligodendrocytes in adult brain. Recently, Wang et al. demonstrated that myelination is highly active in young mice, and diminished myelin renewal contributes to age-related deficits in memory.³ In this study, the authors used a genetic-based tracing approach to detect newly generated oligodendrocytes/myelin in mice and confirmed that new myelin sheath in aged mice was sparsely distributed. The physiological myelination process declined in an age-dependent manner, and notably, decreasing myelination coincided with spatial learning and memory deficits. By genetically deleting Chrm1 in OPCs, the authors enhanced the differentiation of OPCs and myelination in aged mice, which then improved water maze task performance. In addition, pharmacological enhancement of myelination by clemastine also preserved spatial learning in aged mice. The finding that promoting myelination by OPC activation may reverse age-related cognitive decline should provide a new direction in developing therapies for cerebrovascular disease.

Glial cells show high degrees of heterogeneity, and recent advances in transcriptomics now allow us to probe the diversity of their cellular function in the central nervous system. For example, microglial heterogeneity mediates biphasic mechanisms of recovery after brain injury, depending on complex spatiotemporal parameters.⁴ Importantly, microglial heterogeneity may also depend on aging because a recent transcriptomic study revealed that aged microglia showed impaired upregulation of pro-angiogenic genes after stroke.⁵ Similar variations in perivascular astrocytes and pericytes may also mediate function and dysfunction in the neurovascular unit.⁶ For OPCs, it is likely that heterogenous and differentially aging subsets may also exist. OPCs in different regions show different responsiveness to growth factors, and also, physiological properties of OPCs have been found to diversify increasingly depending on age.⁷ However, it still remains unclear whether the diversity of OPC properties reflects subtypes of OPCs with distinct function, especially in the myelination process. A recent paper by Marisca et al. showed the existence and importance of functionally distinct subgroups of OPCs in myelination.⁸ In this study, the authors used the zebrafish system as an experimental model, and by single-cell transcriptomics, calcium imaging and neural activity measurement, they revealed that zebrafish spinal cord has two functionally distinct OPC subtypes with different responses to activity and calcium signaling. The first subgroup forms elaborate networks of processes by less differentiation capacity, and the second subgroup, which is derived from the first one, possesses higher process motility and readily differentiates into myelin-producing mature oligodendrocytes. Further studies are warranted to determine whether these OPC subsets also exist in mammalian systems, and whether they may be differentially regulated in order to boost white matter repair after disease.

Brain plasticity and repair should provide new opportunities for cerebrovascular disease.^9,10 For white matter, this means that a focus on OPCs will be required, especially since the capacity of OPCs for oligodendrocyte repair/recovery would heavily depend on aging.¹¹ Can we stimulate aged and/or diseased OPCs in order to enhance myelination for mitigating cognitive decline? Compared to a large literature in developing systems, the roles of OPCs in adult brain are still relatively understudied. The two papers highlighted in this commentary may provide new models and tools for pursuing OPCs as therapeutic targets in cerebrovascular disease, especially in the context of vascular cognitive impairment in an aging brain.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work is supported in part by the National Institutes of Health.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.