Heterogeneity of mature oligodendrocytes in the central nervous system

Abstract

Mature oligodendrocytes form myelin sheaths that are crucial for the insulation of axons and efficient signal transmission in the central nervous system. Recent evidence has challenged the classical view of the functionally static mature oligodendrocyte and revealed a gamut of dynamic functions such as the ability to modulate neuronal circuitry and provide metabolic support to axons. Despite the recognition of potential heterogeneity in mature oligodendrocyte function, a comprehensive summary of mature oligodendrocyte diversity is lacking. We delve into early 20 th -century studies by Robertson and Río-Hortega that laid the foundation for the modern identification of regional and morphological heterogeneity in mature oligodendrocytes. Indeed, recent morphologic and functional studies call into question the long-assumed homogeneity of mature oligodendrocyte function through the identification of distinct subtypes with varying myelination preferences. Furthermore, modern molecular investigations, employing techniques such as single cell/nucleus RNA sequencing, consistently unveil at least six mature oligodendrocyte subpopulations in the human central nervous system that are highly transcriptomically diverse and vary with central nervous system region. Age and disease related mature oligodendrocyte variation denotes the impact of pathological conditions such as multiple sclerosis, Alzheimer's disease, and psychiatric disorders. Nevertheless, caution is warranted when subclassifying mature oligodendrocytes because of the simplification needed to make conclusions about cell identity from temporally confined investigations. Future studies leveraging advanced techniques like spatial transcriptomics and single-cell proteomics promise a more nuanced understanding of mature oligodendrocyte heterogeneity. Such research avenues that precisely evaluate mature oligodendrocyte heterogeneity with care to understand the mitigating influence of species, sex, central nervous system region, age, and disease, hold promise for the development of therapeutic interventions targeting varied central nervous system pathology.

Figure 1

Timeline of MOL heterogeneity investigations. Diversity in MOLs has been recognized since Rio-Hortega’s discovery of OL/MOL. Advances in methodologies, particularly IHC and cell-based assays throughout the 20^th century allowed further investigation(s) into the varied functions and subpopulations of MOLs, culminating in the emergence of the modern molecular era. RNA-sequencing technologies have allowed scientists to further solidify the existence of diverse MOL functions and subpopulations not only in health but in aging and disease. Created with BioRender.com. EM: Electron microscopy; IHC: immunohistochemistry; MOL: mature oligodendrocyte.

Figure 2

Comparison of human MOL transcriptomes across studies. (A) Heatmap displaying the percent transcriptomic similarity found between healthy adult MOL subpopulations across three independent studies. Yaqubi et al.’s clusters are denoted on the horizontal axis, whereas Seeker et al. and Jäkel et al.’s clusters are listed on the vertical axis. Each box denotes the percent transcriptomic similarity as a rounded value between 0–100%. Color also represents the correlation from blue to red, with blue being a lower correlation and red a higher correlation. (B) DotPlot demonstrating the top 10 biological processes associated with the shared genes between MOL6 and Oligo5. Dot size represents the number of genes associated with a pathway, dot colour represents the adjusted P-value, and position along the x-axis represents the q-value. (C) DotPlot demonstrating the top 10 biological processes associated with the shared genes between MOL1 and OligoA. (D) DotPlot demonstrating the top 10 biological processes associated with the shared genes between MOL2 and OligoF. Unpublished data. MOL: Mature oligodendrocyte.

Figure 3

Summary of age-related changes in MOLs. Schematic diagram providing insight into the age-related alterations seen in MOLs, including largescale WM volume changes, functional diversity, neighboring preferences, transcriptional variations, and developmental disparities among MOLs at various stages of human development. Dashed circles display WM. The red arrow points to a change in WM volume. Created with BioRender.com. MOL: Mature oligodendrocyte; WM: white matter.

Figure 4

Interactions of MOLs with immune cells in MS. Human MOLs express MHC class 1 molecules and are susceptible to targeting by CD8 T cells. They also express receptors enabling interaction with γδ T cells, NK cells, Th17 cells, and CD4 T cells expressing NKG2D, facilitating their adherence and possible downstream harm. Furthermore, human B cells, as well as resident microglia and infiltrating macrophages, have the potential to exacerbate inflammation and damage MOLs, thereby contributing to the progression of MS. Created with BioRender.com. GM-CSF: Granulocyte-macrophage colony-stimulating factor; IFN-γ: interferon-gamma; IL-6: interleukin-6; LT-α: lymphotoxin-α; MHC: major histocompatibility complex; MOL: mature oligodendrocyte; MS: multiple sclerosis; NK: natural killer; TNF-α: tumor necrosis factor-alpha.