Macroglial diversity: white and grey areas and relevance to remyelination

Abstract

Macroglia, comprising astrocytes and oligodendroglial lineage cells, have long been regarded as uniform cell types of the central nervous system (CNS). Although regional morphological differences between these cell types were initially described after their identification a century ago, these differences were largely ignored. Recently, accumulating evidence suggests that macroglial cells form distinct populations throughout the CNS, based on both functional and morphological features. Moreover, with the use of refined techniques including single-cell and single-nucleus RNA sequencing, additional evidence is emerging for regional macroglial heterogeneity at the transcriptional level. In parallel, several studies revealed the existence of regional differences in remyelination capacity between CNS grey and white matter areas, both in experimental models for successful remyelination as well as in the chronic demyelinating disease multiple sclerosis (MS). In this review, we provide an overview of the diversity in oligodendroglial lineage cells and astrocytes from the grey and white matter, as well as their interplay in health and upon demyelination and successful remyelination. In addition, we discuss the implications of regional macroglial diversity for remyelination in light of its failure in MS. Since the etiology of MS remains unknown and only disease-modifying treatments altering the immune response are available for MS, the elucidation of macroglial diversity in grey and white matter and its putative contribution to the observed difference in remyelination efficiency between these regions may open therapeutic avenues aimed at enhancing endogenous remyelination in either area.

Clinically relevant profiles of myelin content changes in patients with multiple sclerosis: A multimodal and multicompartment imaging study

“…This regional difference in remyelination efficiency, which has previously been demonstrated in neuropathological studies, [2][3][4] could result from a more permissive environment for repair in cortical lesions compared to WM plaques. In particular, cortical lesions might be less affected by inhibitory cues from astrocytes, microglia or extracellular matrix 20,21 than WM lesions, and seem to be characterised by an increased availability of oligodendrocyte progenitor cells 21 compared with WM areas. We also found that cortical myelin repair is less efficient in patients with longer disease duration, possibly owing to age-associated changes in the oligodendrocyte precursor cells.…”

Myelin Repair: From Animal Models to Humans

“…There is growing evidence to suggest that OPCs do not constitute a homogeneous cell population (for a review, see Werkman et al, 2020). However, it is difficult to differentiate between real cell diversity and different lineage stages within the same cell population, because only a few studies have shown phenotypic differences to be intrinsic and associated with functional specificity (Foerster et al, 2019).…”

“…Myelin debris are more abundant in white matter, contributing to higher levels of astrocyte activation. In addition, microglial reactivity occurs later and is weaker in the gray matter, resulting in lower levels of cytokine production (Gudi et al, 2009;Buschmann et al, 2012;Werkman et al, 2020). The activation state of astrocytes determines their permissive or inhibitory influence on remyelination.…”

Cellular Senescence in Health, Disease and Aging: Blessing or Curse?

“…For example, a recent study reported an age-associated increase in p16-positive oligodendrocytes, but they were not using senolytic approaches [181]. Brain cell type specific responses to senolytic clearance [181] highlights the heterogeneity of senescent cells even when in the tissue, which may (in part) reflect cell type diversity in complex tissues as the brain [59,182,183].…”

“…Brain cancers such as gliomas are infilwith glioma associated microglia (GAM) that are recruited and reprogrammed by glioma cells [179,180]. These microglia increase glioma growth due to their decreased tumor sensing and immune response, while releasing mitogens and invasion promoting [181,182]. Given the role of microglia in neuroprotective and immune-modulatory functions, aberrant microglial function has also been linked to neurological diseases such as AD and PD [165].…”