Molecular Mechanisms of Oligodendrocyte Regeneration in White Matter-Related Diseases.

Ryo Ohtomo,Atsushi Iwata,Ken Arai

doi:10.3390/ijms19061743

Abstract

Even in adult brains, restorative mechanisms are still retained to maintain the microenvironment. Under the pathological conditions of central nervous system (CNS) diseases, several immature cells in the brain would be activated as a compensative response. As the concept of the neurovascular unit emphasizes, cell-cell interactions play important roles in this restorative process. White matter damage and oligodendrocyte loss are representative characteristics for many neurodegenerative diseases. In response to oligodendrocyte damage, residual oligodendrocyte precursor cells (OPCs) initiate their proliferation and differentiation for the purpose of remyelination. Although mechanisms of oligodendrogenesis and remyelination in CNS diseases are still mostly unknown and understudied, accumulated evidence now suggests that support from neighboring cells is necessary for OPC proliferation and differentiation. In this review, we first overview basic mechanisms of interaction between oligodendrocyte lineage cells and neighboring cells, and then introduce how oligodendrogenesis occurs under the conditions of neurodegenerative diseases, focusing on vascular cognitive impairment syndrome, Alzheimer’s disease, and multiple sclerosis.

Highlights

It has been nearly 20 years since the neurovascular unit (NVU), a conceptual structural unit composed of neurons, glial cells, vascular endothelial/smooth muscle cells, pericytes, and extracellular matrix, was proposed as a new paradigm for the investigation of stroke [1,2]
As primary etiologies for central nervous system (CNS) diseases are most likely to be found in the gray matter, past studies mainly focused on the protection and recovery of neurons that lie within the gray matter
Besides decreases in cerebral blood flow (CBF), a recent pathological study reported that parietal white matter degeneration in Alzheimer’s Disease (AD) patients could partially be attributed to Wallerian-like degeneration, which is a secondary axonal loss due to neuronal loss caused by the accumulation of phosphorylated tau in the cortex [80]

Summary

Introduction

It has been nearly 20 years since the neurovascular unit (NVU), a conceptual structural unit composed of neurons, glial cells (astrocytes, microglia, oligodendrocytes), vascular endothelial/smooth muscle cells, pericytes, and extracellular matrix, was proposed as a new paradigm for the investigation of stroke [1,2]. In an animal model of acute spinal cord injury, transplantation of cultured astrocytes facilitated the myelin restoration in the demyelinated lesion via accelerating the proliferation of endogenous OPCs [15] Microglia, another sub-type of glial cells, have an important interaction with oligodendrocyte lineage cells. Recent basic studies using rodent models of VCI have made several important findings for understanding the pathophysiology of VCI [49,50,51,52] Those rodent models replicate representative pathological white matter changes observed in VCI patients, including the disruption of the blood-brain barrier, glial activation, oxidative stress, demyelination with axonal damage, and increase of OPCs in demyelinated lesion (Table 1). We introduce some key findings from recent studies using the mouse hypoperfusion model, focusing on oligodendrocyte protection and restoration

White matter legion Cognitive dysfunction

Conclusions