Adult Neoneurogenesis and Oligodendrogenesis in Multiple Sclerosis: A Systematic Review of Human and Animal Studies

Abstract

Introduction:

The subventricular zone promotes remyelination through activation differentiation of oligodendroglial precursor cells (OPCs) and neural stem cells (NSCs) into mature oligodendrocytes and thus in the adult brain. In multiple sclerosis (MS) this regenerative capability is halted resulting in neurodegeneration. We aimed to systematically search and synthesize evidence on mechanisms and phenomena associated with subventricular zone (SVZ) dysfunction in MS.

Materials and Methods:

Our systematic review was reported according to the PRISMA-ScR statement. MEDLINE, SCOPUS, ProQuest, and Google Scholar were searched using the terms “subventricular zone” and “multiple sclerosis,” including English-written in vivo and postmortem studies.

Results:

Twenty studies were included. Thirteen studies on models of experimental autoimmune encephalomyelitis (EAE) reported among others strong stathmin immunoreactivity in the SVZ of EAE models, the role of MOG immunization in neurogenesis impairment, the effect of parenchymal OPCs and NSCs in myelin repair, and the importance of ependymal cells (E1/E2) and ciliated B1 cells in SVZ stem cell signaling. CXCR4 signaling and transcriptional profiles of SVZ microglia, Gli1 pathway, and galactin-3 were also explored. Studies in humans demonstrated microstructural SVZ damage in progressive MS and the persistence of black holes near the SVZ, whereas postmortem confirmed the generation of polysialic acid–neural cell adhesion molecule and NG2-positive progenitors through SVZ activation, SVZ stathmin immunoreactivity, Shh pathway, and Gal-3 upregulation.

Discussion:

Oligodendrogenesis defects translate to reduced remyelination, a hallmark of MS that determines its end-phenotype and disease course.

Conclusion:

The role of inflammation and subsequent SVZ microenvironment disruption is evident in MS pathology.

Impact Statement

In this work, the role of impaired adult neurogenesis and oligodendrogenesis in the pathophysiology of multiple sclerosis is explored. We herein synthesize the state of the art on human studies and animal models that involve the subventricular zone (SVZ), a hub critical for both neoneurogenesis and oligodendrogenesis. Our findings highlight defects that may affect both processes in the long term and synergistically shape the pathophysiology of multiple sclerosis. Furthermore, the exposure of this delicate system and oligodendroglia progenitors to peripheral inflammation may be a plausible mechanism of myelin restorative failure following demyelination, and of impaired olfactory neurogenesis in multiple sclerosis.