Macroglial diversity: white and grey areas and relevance to remyelination

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.