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.

Introduction

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by neuroinflammation, demyelination, and axonal degeneration. Although most patients are initially diagnosed with relapsing/remitting MS (RRMS), many patients have worsening symptoms over time and almost half of them will develop secondary progressive MS (SPMS) within 15 years and up to two-thirds after 30 years leading to the gradual progression of their neurological function and limitation of their daily activities (Inojosa et al., 2021). In a subset of patients, the disease manifests with a progressive course at diagnosis, characterized as primary progressive MS (PPMS), although SPMS and PPMS share similar underlying pathologies (Lassmann, 2019). To date, there are multiple treatment options with great efficacy for the management of RRMS, although therapeutic options for the progressive course of the disease still remain limited (Lassmann, 2019). The mechanisms through CNS respond to peripheral immune infiltration may play a fundamental role in understanding MS progression. Microglia, the core immune cells in active MS lesions (Kuhlmann et al., 2017), interfere with other CNS cells and can rapidly proliferate and turnover in response to CNS insults and regulate in that way CNS homeostasis (Füger et al., 2017; Hagan et al., 2020).

A growing body of evidence suggests the coexistence of defects in remyelination and neoneurogenesis in MS (Chang et al., 2008). The core CNS cells in this process are microglia, which regulate oligodendroglial precursor cells’ (OPCs’) homeostasis and also contribute to inflammatory and degenerative axonal damage. In the adult brain, partial replacement of lost oligodendrocytes can occur through activation and differentiation of resident oligodendroglial precursor cells (OPCs) and neural stem cells (NSCs) into mature oligodendrocytes, which then remyelinate the demyelinated axons (Gruchot et al., 2019). However, for multiple reasons, this process is not always efficient, resulting in the diminishing regenerative capability of these cells over time. Adult human neoneurogenesis occurs in two sites: the hippocampi, the subventricular zone/subependymal/stromal zone, and the striatum (Chang et al., 2008; Ernst et al., 2014; Lazarov and Hollands, 2016). Furthermore, oligondrocyte progenitors in the SVZ determine the efficiency of CNS myelination and myelin repair (Gruchot et al., 2019). It is thus a central mechanism affected by MS, integral to its definition.

We therefore attempt to synthesize the evidence on mechanisms and phenomena associated with SVZ dysfunction/impairment in MS into a pathogenetic model, through a systematic review of the literature.

Methods

We followed the PRISMA guidelines for conducting and reporting our systematic review.

Search strategy and information sources

MEDLINE and SCOPUS were searched from inception to June 4, 2023. We used both keywords and controlled vocabulary for the terms: “subventricular zone,” SVZ, and “multiple sclerosis.” We employed forward and backward searching, as well as hand searching for eligible studies. ProQuest and Google Scholar were also hand-searched for gray literature. Our search strategy for MEDLINE’s database is presented in Table 1.

Table 1.

The Complete Search Strategy for MEDLINE (June 4, 2023)

Search	Query	Items found
#1	Search: “Multiple Sclerosis” OR MS OR “Multiple Sclerosis”[Mesh] OR “Multiple sclerosis”[tw]	590,931
#2	Search: “subventricular zone” OR SVZ OR “Lateral Ventricles”[Mesh] OR “subventricular zone”[tw]	6,846
#4	#1 AND #2	178

Eligibility criteria

Our systematic review included both studies conducted in humans (in vivo and postmortem) and in animals. Patients had to have a diagnosis of MS based on the international McDonald criteria or an autopsy-confirmed diagnosis. Similarly, experimental models of MS had to be used in studies with animals. Both quantitative and qualitative imaging, histological, and immunohistochemical methodologies were eligible for inclusion. Finally, the articles included had to be peer-reviewed and written in English. Studies were excluded if they did not fit the concept described above, i.e., patients with demyelinating disease but without a diagnosis of MS, animal models of diseases other than MS, studies evaluating neural stem cells and neurogenesis niches other than SVZ, or articles whose full reports were not written in English.

Data management

We used the Systematic Review Accelerator (SRA) (Clark et al., 2020) for deduplication. The screening of the articles was done with the use of the web-based application Rayyan (Ouzzani et al., 2016) 2.4 Selection of studies. Two independent reviewers (AL and VST) initially screened abstracts and titles of all search results for eligibility. Selected articles’ full texts were then screened as well. During the screening process, the two reviewers were blind to each other’s decisions. Discrepancies were discussed until a consensus was reached. Reference manager “Mendeley” (Desktop version 1.19.8) was used for eligible studies. We constructed the PRISMA flow diagram using an interactive R-based online tool developed by Haddaway et al., (2022).

Data extraction

Due to the expectation of heterogeneous study methodologies and results, data extraction for our review took place after the categorization of studies by type i.e., studies conducted in humans (in vivo and postmortem) and studies conducted in animals. For all studies, the first author and year of publication were extracted. Regarding in vivo studies, we extracted data about patients’ characteristics (sample size; MS types studied; age, number, and percentage of female patients participating; disease duration; and EDSS scores), imaging/MRI characteristics (MRI protocol, field strength, section thickness), as well as main results. Reliability data (intra- and inter-rater agreement) were also extracted if reported. In postmortem studies instead of imaging characteristics, we extracted data concerning methodology (histological and immunohistochemical analyses, immunostaining, etc.); the rest of the data extraction was identical to in vivo studies. For animal studies, animals’ characteristics (species/strain, sex, age, demyelination/EAE induction method, clinical scoring), methodology reported, and main study results were extracted. Data extraction was done by two independent reviewers separately and conflicts were resolved after discussion until a consensus was reached.

We presented quantitative variables in mean and standard deviations. If these were not provided in the original studies, they were calculated by us, using information about the sample provided in tables of supplementary material or reported in the publications of the original studies (age, disease duration, etc.). In case no such data were provided, we marked them as “not reported.”

Data synthesis

We created tables to summarize methodological characteristics and results from all selected studies and we proceeded to qualitative synthesis. This study used aggregate data where possible, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (Page et al., 2021). No quantitative synthesis was attempted due to the expected inherent heterogeneity in our review’s conceptual framework.

Results

Our search strategy identified a total of 576 articles, of which 557 were excluded during the eligibility assessment. One article was identified through screening of the reference lists of the included articles. Ultimately, a total of 20 studies, published between 2002 and 2023, were included in the present review (Banisadr et al., 2011; Cellerino et al., 2023; Chang et al., 2002, 2008; Gould et al., 2018; James et al., 2016; Liu et al., 2005; Moyon et al., 2023; Nait-Oumesmar et al., 2007; Oreja-Guevara et al., 2017; Papadopoulou et al., 2014; Payne et al., 2012; Petratos et al., 2004; Pourabdolhossein et al., 2017; Rasmussen et al., 2011; Samanta et al., 2015; Sherafat et al., 2012; Starossom et al., 2011; Tepavčević et al., 2011; Wang et al., 2008). The study population included animal models with experimental autoimmune encephalitis (EAE) in 13 studies (Banisadr et al., 2011; Gould et al., 2018; James et al., 2016; Liu et al., 2005; Moyon et al., 2023; Payne et al., 2012; Pourabdolhossein et al., 2017; Rasmussen et al., 2011; Samanta et al., 2015; Sherafat et al., 2012; Starossom et al., 2011; Tepavčević et al., 2011; Wang et al., 2008), brain tissues of patients with MS in five studies (Chang et al., 2008; Chang et al., 2002; Nait-Oumesmar et al., 2007; Oreja-Guevara et al., 2017; Petratos et al., 2004), animal models with EAE and brain tissues of patients with MS in three studies (James et al., 2016; Liu et al., 2005; Wang et al., 2008), and human subjects with MS in two studies (Cellerino et al., 2023; Papadopoulou et al., 2014). The selection process is shown in Figure 1 (PRISMA chart).

FIG. 1.

PRISMA flow chart. SVZ, subventricular zone.

Animal studies

Evidence from animal studies supports the significant role of SVZ in the neurogenesis and oligodendrocyte maturation in animal models of MS-like pathology (Table 2). In an animal study, authors used a mouse model of MS to assess the therapeutic potentials of neural stem cells (NSCs) derived from embryonic stem cells (ESCs) compared with that of primary NSCs derived from the SVZ and found no beneficial effect on the clinical course of chronic progressive disease of rMOG-induced EAE in both treatment options (Payne et al., 2012). In a study, authors induced demyelination by stereotaxical injection of lysophosphatidylcholine (LPC) into the corpus callosum of 30 adult female Sprague–Dawley rats and investigated the potential effect of electromagnetic field stimulation (EMFS) on the remyelination process and the possible role of endogenous NSCs derived from SVZ (Sherafat et al., 2012). EMFS led to a significant reduction of the extent of demyelinated plaques and increase of the level of myelin basic protein (MBP) within the lesion area 2 and 4 weeks, respectively, after the induction of lesion. Also, SVZ BrdU- and nestin-positive cells were increased, 1 and 2 weeks, respectively, after the induction of lesion, indicating the potential effect of EFMS on the proliferation and migration of NSCs and the repair of myelin when demyelinating conditions are present.

Table 2.

Animal Studies of Subventricular Zone

	Objective	Animals’ characteristics		Demyelination induction method	Clinical scoring	Methodology	Main results
	Objective	Species (n), sex	Age	Demyelination induction method	Clinical scoring	Methodology	Main results
Liu et al., 2005	To investigate the expression of stathmin in conditions of myelin dysfunction	C57BL/6 mice (n = 8), sex NR	8 weeks old	Ethidium bromide	NR	Primary cultures and immunochemistry of oligodendrocyte progenitors from the neonatal rat brain; Ethidium bromide injection in mice; Immunochemistry of brain sections of adult mice	Increased stathmin-expressing PSA-NCAM⁺ cells in demyelinated lesions. Low levels of stathmin during remyelination or in the absence of inflammatory conditions.
Payne et al., 2012	To evaluate the therapeutic effects of systemic administration of ES-derived NSCs in a rMOG-induced chronic progressive murine model of MS and to compare it with SVZ-derived NSCs	C57Bl/6 mice (number NR), female	8–10 weeks old	rMOG/complete Freund’s adjuvant/mycobacterium tuberculosis/B. pertussis toxin	0–5 scale*	Cell culture; Gene expression analysis; Electrophysiological recordings; Cell surface expression analysis; EAE induction; Cell transplantation (iv or ip—days 8, 10, 12); In-vivo tracking of GFP⁺ GS-N cells; Histological analysis	IV-injected NSCs did not affect disease outcomes, due to lack of cell surface homing molecules.
Sherafat et al., 2012	To assess the effects of electromagnetic fields on remyelination in an animal model of MS, as well as to assess the role of SVZ-reside stem cells and their migration into the lesion	Sprague-Dawley rats, (n = 30), female	8–10 weeks old	Stereotaxical LPC injection into the corpus callosum	NR (demyelinationintensity was determined in brain tissues during myelin staining process)	EMFs (60 Hz; 0.7 mT) were applied for 2 h twice a day for 7, 14, or 28 days postlesion; BrdU labeling and immunostaining against nestin; MBP and BrdU were used for the assessment of the amount of neural stem cells within the tissue, remyelination patterns, and tracing of proliferating cells, respectively.	Use of EMFs showed significant reduction of demyelination and increase of within-lesion MBP staining level on days 14 and 28 postlesion. Increased number of BrdU⁺ and nestin⁺ cells in the area between SVZ and lesion on days 7 and 14 was also observed. Results indicating EMF-potentiated neural stem cell proliferation and migration and enhancement of myelin repair.
Tepavčević et al., 2011	To examine SVZ function in a mouse model of forebrain-targeted EAE	C57BL/6 mice, (number NR), female	9–10 weeks old	Targeted EAE induction MOG subclinical immunization, 16–20 days later: stereotaxical injection of mouse TNF-α, IFN-γ into the corpus callosum. Experimental groups included sham controls (saline-injected) cytokine-injected controls (nonimmunized animals injected with cytokine cocktail and immunization controls (immunized noninjected mice)	NR	Targeted EAE induction; Ultrastructural SVZ analysis using ultrathin sections and a transmission electron microscope; Immunohistochemistry; SVZ/OB cell type quantification; Olfaction study (olfactory discrimination, short-term olfactory memory, rewarded olfactory discrimination, long-term memory test)	SVZ niche inflammation associated with amplification of pro-oligodendrogenic responses and increased populations of Olig2-expressing type C cells and SVZ-derived Olig2+ cells in the corpus callosum. Neuroblast reduction in tEAE mice compared with controls leading to persistent reduction in olfactory bulb neurogenesis and impaired long-term olfactory memory, resembling MS pathology (observed only with prior MOG immunization, due to either differences in inflammation cells infiltration or choroid plexus changes caused by the active immune response with subsequent alterations of NSCs within the SVZ niche.
Moyon et al., 2023	To investigate the role of parenchymal OPCs and NSCs in myelin repair process in cuprizone-induced demyelination mice models	Heterozygous inducible NG2^CreERTM ^/+ ;Nestin^FlpoERT ^2/+;R26^RCE ^/ ^FSF ⁻ ^tdT used as dual reporter mice	NR	Cuprizone-induced (0.2% cuprizone pellets for 6 weeks) one week after a 14-day regimen of ip tamoxifen injection	NR	Immunohistochemistry and myelin staining; Examination of fluorescent slides on fluorescence microscope; Examination of eriochrome cyanine-stained sections	Despite parenchymal OPCs being the main cells for myelin repair in the corpus callosum compete with NSCs, which are also recruited and differentiate into OLs in the corpus callosum, and even in areas distant to SVZ, for remyelination of damaged white matter lesions
Gould et al., 2018	To evaluate early cellular alterations contributing to progressive pathology in Proteolipid protein-null (Plp1-null) mice	Plp1-null (n = 10) and wild type (n = 10), male (for the study of axonal disruption Plp1-null mice crossed with Thy-1-YFP mice were used)	NR	Genetic deletion of Plp1 by crossing Plp1-null heterozygous females with wild-type C57BL/6 males (PLP1 gene is found in the X chromosome)	NR	Imaging of brain samples with cleared tissue digital scanned light-sheet microscopy; EDU labeling and quantification of EDU+ cells; Immunohistochemistry; Apoptotic cell labeling; Digital image acquisition and analysis of tiled sagittal sections and cleared tissue sections; Corpus callosum electrophysiology; Behavioral assessment with a commercial automated animal tracking software and a camera (rotarod, swimming, gait analysis, open field, zero maze, Y maze, marble burying, puzzle box, go-no-go odor discrimination task, Olfactory habituation/dishabituation); Modeling of piriform cortex neural activity; Tetrode construction and implementation surgery; Recording	Μyelin damage was associated with elevated proliferation in the SVZ and generation of new OLs, accompanied by behavioral and cellular alterations and cognitive impairments, which occur before axonal derangements. Thus, the protective role of SVZ is supported in reducing behavioral effects of the absence of PLP1 in myelin.
Pourabdolhossein et al., 2017	To investigate the role of ependymal cells (E1/E2) and ciliated B1 cells in the context of inflammatory demyelination in a forebrain-targeted model of EAE	C57BL/6 mice (n = 75), female	9–10 weeks old	MOG peptide in CFA, 16–20 days later: stereotaxic injection of mouse TNF-a and IFN-g into the corpus callosum		Targeted EAE induction; Whole mount preparations of lateral ventricles-immunohistochemistry; Fixed frozen tissue processing-immunochemistry; Electron microscopy processing and ultrastructural analysis of the SVZ; Proliferation and tracing assays; Analysis of proliferation of different cell types within the SVZ niche; Analysis of basal body patch	Demyelination was associated with SVZ stem cell proliferation and early ventricular modifications in ciliated B1 cells and ependymal cells, suggesting a role of these cells in SVZ stem cell signaling.After tEAE, an early and transient decrease in the number of pinwheels, B1 cells, and E2 cells was noted, simultaneously with tEAE-induced SVZ stem cell proliferation, followed by B1/E2 cell recovery. E1 cells showed important morphological modifications possibly in the context of protective mechanisms against ventricular insults. The significant ventricular modifications in ciliated cells in response to tEAE suggest a possible role in SVZ stem cell signaling both during development and inflammatory demyelination.
Banisadr et al., 2011	To investigate the role of CXCR4 signaling in the regulation of OPs’ migration in the corpus callosum after their transplantation into the lateral ventricle	SJL/J mice, female	6–7 weeks old	EAE induction using mycobacterium tuberculosis, PLP	0–5 scale*	Cultures of mouse oligospheres (populations of free-floating mouse OPs); RT-PCR for total RNA isolation and genomic DNA elimination; Immunohistochemistry for oligodendrocyte identification; Downregulation of CXCR4 using shRNA-based RNA interference (RNAi); Quantitative PCR using primers for chemokine receptors; EAE induction, stereotaxic injections; Histology on confocal microscope with measurement of Ops’ migration distance from wild-type and CXCR4 knockout mice; Immunohistochemistry for cell characterization	Migratory capacity of transplanted OPs was higher in mice with EAE compared with naive mice and was confined within areas of demyelination of white matter through chemokine SDF-1 signaling through its receptor CXCR4 in the SVZ, which was also higher in EAE models. OPs differentiated into mature oligodendrocytes in vivo. Downregulation of chemokine receptor CXCR4 in the OPs partially inhibited migration, indicating the role of SDF-1/CXCR4 signaling in OPs migration.
Starossom et al., 2011	To investigate whether microglia play a beneficial or detrimental role on the neural stem cell environment during the course of EAE, by analyzing gene expression of isolated, flow sorted SVZ resident microglia during acute and chronic EAE.	SJL/J mice (n = 120), female		Immunization with PLP139-151 (acute EAE: peak of the disease, around 13 dpi, minimal score of 2; chronic EAE: after first relapse, 50–60 dpi, minimal score of 1.5)	0–5 scale*	EAE induction; CD11b+/CD45lo microglia isolation of SVZ tissue; Microarray analysis; Gene ontology, Canonical pathway and functional network analysis using IPA tools; Quantitative real-time RT-PCR; Coimmunostaining and confocal microscopy; Histology	Microglia express gene signatures specific for disease phase (acute or chronic), which correspond to unique gene ontology functions and genomic networks and affect the SVZ microenvironment. At the acute phase they exhibited both support of inflammation and secretion of molecules associated with neural stem cell support. Distinct transcriptional networks of microglia activation were shown in vivo, suggesting mediation of injury or repair.
Rasmussen et al., 2011	To investigate the role of microglia activation in SVZ stem cell responses in EAE, as well as to test the hypothesis that minocycline could have an effect on SVZ dysfunction through microglia inactivation.	SJL/J mice		PLP139–151 sc injection emulsified in complete Freund's adjuvant, mycobacterium tuberculosis, pertussis toxin i.p. at the time of immunization and 48 h later	NR	EAE induction; In vivo analysis of SVZ stem cells proliferation and quantification (using i.p. BrdU injections); Electron microscopy processing and quantification (3 mice from each group); Confocal analysis of regions of interest around the lateral ventricle; Reconstruction and pixel intensity analysis (4 mice per group); In vivo minocycline regimen or vehicle PBS on 20 dpi (10 animals per group); In vitro effect of minocycline on isolated microglia and staining of differentiated neural stem cells	In vivo injection of minocycline showed increased proliferation of NSCs in both naive and EAE models and decreased cortical and periventricular pathology in the chronic phase of EAE. Treatment with minocycline also improved the proliferation of progenitors derived from SVZ and their differentiation into mature oligodendrocytes.
Wang et al., 2008	To study the regulation of inflammatory injury of NSCs intrinsic properties through investigation of the role of the Shh-Gli1 pathway and its association with inflammatory cytokines.	C57BL/6 and C57BL/6-Tg (UBC-GFP) mice		MOG-TCR transgenic 2D2 mice	NR	Isolation of E14.5 or E12.5 NSCs from cerebral cortices of timed C57BL/6 or UBC-GFP mouse embryos; Astroglia isolation from the neonatal mice hemispheres on postnatal day 0 (for cytokine treatment experiment); NSC differentiation in the presence of Shh neutralizing antibodies or control IgG; Gli1 gene silencing	Marked upregulation of Shh by reactive and perivascular microglia was shown in early phases of EAE (and active MS lesions), with involvement in NSC differentiation toward neurons and oligodendrocytes. However, Gli1 expression was significantly reduced in the OPCs of the spinal cord after EAE onset and in chronic active and inactive lesions of MS patients. Th1 cytokine IFN-γ induced Shh expression in astroglia, while suppressing Gli1 expression in NSCs, inhibiting Shh-mediated NSC differentiation.
Samanta et al., 2015	To examine remyelination by studying the Shh-responsive (i.e., Gli1+) pool of NSCs in the ventral SVZ	Gli1^CE mice, female	8 weeks old	PLP immunization	EAE induction kit (Hooke Laboratories) inclusion criteria of clinical score of 2 or above for final analysis (n = 9/group)	Tamoxifen was used for fate mapping (permanent expression of cytoplasmic green fluorescent protein in all Gli1-expressing cells); GANT61 or vehicle-delivered administration for 4 weeks into the lateral ventricle of Gli1CE/+mice through mini-osmotic pump; Immunostaining; Flow cytometry; EdU labeling; EAE induction with the use of PLP; electron microscopy; Quantitative PCR	Genetic or pharmacological Gli1 inhibition enhanced the recruitment of NSCs in the SVZ, their differentiation into oligodendrocytes, and their migration into demyelinating lesions in the forebrain. Interestingly, the loss of canonical Shh pathway signaling was not effective, identifying the specificity of Gli1 on myelin repair.
James et al., 2016	To study the role of galectin-3, a proinflammatory protein, in SVZ proliferation in the context of MS-induced inflammation	Gal-3^−/− mice, female	6–8 weeks old	Infection with TMEV	NR	Encephalomyelitis induction; Immunohistochemistry; Astrocyte cultures; RT-PCR; ELISA for analysis of tissue protein levels; Primary mouse macrophage isolation; xCELLIgence real-time chemotaxis assay for mouse macrophage chemotaxis; Cell quantification and analysis	Gal-3 expression was enhanced in periventricular regions of TMEV-infected mice. SVZ chemokine (CCL2, CCL5, CCL8, and CXCL10) expression in wild-type (WT) mice after TMEV infection was also increased compared with those with loss of Gal-3. Loss of Gal-3 was associated with decreased immune cell migration into the SVZ and increased population of progenitors into the CC. Gal-3 blocking resulted in restored SVZ proliferation and increased numbers of progenitors in the CC of TMEV-infected mice, suggesting a fundamental role of Gal-3 in the modification of SVZ niche in response of demyelination.

*0–5 scale (0: no disease, 1: loss of tail tone, 1.5: poor righting ability, 2: hindlimb weakness. 3: hindlimb paralysis, 4: hindlimb paralysis and fore limb weakness, 5: moribund).

NR, not reported; MS, multiple sclerosis; EAE, experimental encephalomyelitis; PSA-NCAM, polysialic acid–neural cell adhesion molecule; GFP, green fluorescent protein; rMOG, recombinant myelin oligodendrocyte glycoprotein; NSCs, neural stem cells; LPC, lysophosphatidylcholine; ES, embryonic stem (cells); BrDU, bromodeoxyuridine / 5-bromo-2'-deoxyuridine; EMFs, electromagnetic fields; MBP, myelin basic protein; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ; OB, olfactory bulb; OPCs, oligodendrocyte progenitor cells; i.p., intraperitoneal; i.v., intravenous; sc, subcutaneous; OLs, oligodendrocytes; EDU, 5-ethynyl-2′-deoxyuridine; OPs, oligodendrocyte progenitors; shRNA, short hairpin RNA; dpi, day postimmunization; IPA, Ingenuity Pathways Analysis; Shh-Gli1, sonic hedgehog-Gli1 (pathway); GANT61, a small molecule inhibitor of Gli1; TMEV, Theiler’s murine encephalomyelitis virus; Gal-3, galectin-3.

Liu et al. investigated the expression of stathmin, a developmentally regulated tubulin-binding protein, in the brain of MS patients and in animal models of demyelination (Liu et al., 2005). Strong stathmin immunoreactivity was documented in multipotential progenitors in the SVZ of adult mice. Authors yielded an increasing number of stathmine expressing polysialic acid–neural cell adhesion molecule (PSA-NCAM)+ cells in the context of demyelinating conditions, while during remyelination in the absence of inflammatory process, the expression of stathmin was decreased in mature oligodendrocytes.

SVZ function was also examined in mice, which were targeted with an MS-like pathology to the forebrain (Tepavčević et al., 2011). The authors found that inflammation in the SVZ niche was associated with amplification of pro-oligodendrogenic responses and increased populations of Olig2-expressing type C cells and SVZ-derived Olig2+ cells in the corpus callosum. However, olfactory bulb neuroregeneration was diminished, potentially accounting for long-term olfactory and memory deficits, resembling those observed in MS patients. Interestingly, neurogenesis impairment was observed only when mice were immunized with myelin oligodendrocyte glycoprotein (MOG) before injection, probably due to choroid plexus changes yielded due to immune response and alterations of NSCs within the SVZ niche.

In a study, authors investigated the role of parenchymal OPCs and NSCs in the myelin repair studying mice models in which demyelination was induced with cuprizone (Moyon et al., 2023). POPCs being the main cells for myelin repair in the corpus callosum compete with NSCs, which are also recruited and differentiate into OLs in the corpus callosum, and even in areas distant to SVZ, for remyelination of damaged white matter lesions.

The results of mild myelin disruption were explored in protein proteolipid protein (PLP1)-null mice, where authors found that myelin damage is associated with elevated proliferation in the SVZ and generation of new OLs, accompanied by behavioral and cellular alterations and cognitive impairments, which occur before axonal derangements (Gould et al., 2018). This evidence supports the protective role of SVZ in reducing the behavioral effects of the absence of PLP1 in myelin.

The role of ependymal cells (E1/E2) and ciliated B1 cells in the context of inflammatory demyelination was investigated in a forebrain-targeted model of experimental autoimmune encephalomyelitis (tEAE) (Pourabdolhossein et al., 2017). Authors found that demyelination was associated with SVZ stem cell proliferation and early ventricular modifications in ciliated B1 cells and ependymal cells, suggesting a role of these cells in SVZ stem cell signaling.

Banisadr et al. commented on the role of CXCR4 signaling in regulating the migration of transplanted OPs from the SVZ into the corpus callosum (CC) of adult mice with and without MS-like pathology (Banisadr et al., 2011). Interestingly, in the EAE models, the migratory capacity of OPs was higher compared with naive mice and was confined within areas of demyelination of white matter through chemokine SDF-1 signaling through its receptor CXCR4 in the SVZ, which was also higher in EAE models. Furthermore, authors downregulated the chemokine receptor CXCR4 in the OPs and found that migration was partially affected, indicating that there are possibly other factors cofounding in the migration of OPs.

Starossom et al. analyzed the transcriptional profile of SVZ microglia in mice models with MS-like pathology during the acute and chronic phase of the EAE (Starossom et al., 2011) and yielded distinct transcriptional networks of microglia activation due to demyelination, which are closely associated with alterations in endogenous NSCs repair mechanism and niche activity, suggesting microglia as mediators of white matter damage or repair of myelin. In particular, it was documented the dual role of microglia in supporting and orchestrating the inflammatory process and secreting molecules that actively support NSC functions. Despite the loss of NSC activity during the chronic phase, this phenomenon tended to be reversible, yielding the role of the niche microenvironment in stem cell dysfunction. Interestingly, the authors found independent genomic signatures of microglia from acute and chronic EAE. The NSC niche dysfunction during the chronic phase was also yielded by Rasmussen et al. in a relapsing–remitting model of EAE, and correlated with microglia activation (Rasmussen et al., 2011). Authors investigated the role of minocycline, an inhibitor of microglia activation, and found an increase of NSC proliferation in both naive and EAE models and a decrease of cortical and periventricular pathology in the chronic phase of EAE after in vivo injection with minocycline. Treatment with minocycline also improved the proliferation of progenitors derived from SVZ and their differentiation into mature oligodendrocytes.

The role of sonic hedgehog (Shh)-Gli1 pathway on the mobilization of neural stem cells during demyelination was investigated in two studies, where mice models with EAE (Samanta et al., 2015; Wang et al., 2008) and brain species of patients with MS were examined (Wang et al., 2008). Samanta et al. explored mice models with EAE and documented that the recruitment of NSCs in the SVZ, their differentiation into oligodendrocytes, and their migration into demyelinating lesions in the forebrain is enhanced by inhibition of Gli1, suggesting a new therapeutic target for demyelination (Samanta et al., 2015). Interestingly, the loss of canonical Shh pathway signaling was not effective, identifying the specificity of Gli1 on myelin repair. In a study by Wang et al., although Shh signaling was upregulated by type 1T helper (Th1) cytokine interferon-gamma (IFN-γ) during early inflammation of models EAE and those with active lesions of MS, expression of Gli1 was significantly reduced in spinal cord OPCs after onset of EAE and in chronic active and inactive lesions from MS brain (Wang et al., 2008). Importantly, authors showed that astroglia contributes to the establishment of ectopic niches in the CNS and produce Shh, although chronic inflammation impairs effective myelin repair.

Finally, the role of galectin-3 (Gal-3), a proinflammatory protein, in the modulation of SVZ was investigated by James et al. using a murine model with MS and postmortem brain samples (James et al., 2016). Gal-3 expression was enhanced in periventricular regions of a murine model, after Theiler’s murine encephalomyelitis virus (TMEV) infection. SVZ chemokine (CCL2, CCL5, CCL8, and CXCL10) expression in wild-type (WT) mice after TMEV infection was also increased compared with those with loss of Gal-3, indicating that loss of Gal-3 is associated with reduced chemokine expression. Furthermore, the authors demonstrated that loss of GAL-3 (Gal-3^−/−) was associated with decreased immune cell migration into the SVZ and increased population of progenitors into the CC. Mice with TMEV infection showed a restored SVZ proliferation and increased numbers of progenitors in the CC when Gal-3 was blocked, suggesting a fundamental role of Gal-3 in the modification of SVZ niche in response of demyelination.

Human studies

Limited data from human studies document the role of the SVZ in neoneurogenesis and oligodendrocyte maturation in MS (Table 3). In a case–control study, Cellerino et al used advanced MRI techniques and explored in vivo SVZ micro- and macro- characteristics between patients with RRMS (n = 101), PMS (n = 50), and controls (n = 20) and found significant microstructural changes in patients with MS (Cellerino et al., 2023). In particular, the microstructural damage of SVZ was higher in patients with PMS, even adjusted for age, indicating that SVZ involvement is related to disease stage. These abnormalities were mostly evident in the progressive phases of MS and significantly associated with caudate microstructural damage along with reduced volumes and higher clinical disability scores, indicating the neuroprotective role of SVZ in MS patients.

Table 3.

Studies of Subventricular Zone in Human Subjects

	Objective	Patients’ characteristics	Age, mean (SD)	Female sex, n (%)	Disease duration, mean (SD)	EDSS, mean (SD)	MRI characteristics	Field strength / section thickness	Reliability	Main results
	Objective	Number	Age, mean (SD)	Female sex, n (%)	Disease duration, mean (SD)	EDSS, mean (SD)	MRI Protocol	Field strength / section thickness	Intra- and Inter-rater	Main results
Cellerino et al., 2023	To characterize SVZ in-vivo in MS patients	n = 151PPMS (n = 32)SPMS (n = 18)RRMS (n = 101)	43 (11)	99 (65.5%)	43 (9)	2.5 (1.16)	Diffusion MRI for the study of microstructural injury—use of SMT metrics: INTRA, EXTRATRANS, EXTRAMD	3 Tesla	NR	Caudate and thalamus nuclei volumes differed among HC, RRMS, and PMS patientsHigher EXTRAMD and EXTRATRANS in PMS in comparison to RRMS and HC. INTRA was significantly lower in PMS compared with HC. NA-SVZ metrics significantly predicted caudate atrophyNA-SVZ metrics EXTRAMD and EXTRATRANS was significantly correlated to RRMS patients’ EDSS
Papadopoulou et al., 2014	To explore the correlation of lesion-to-ventricle (LV) distance and the presence of persistent new black holes on brain MRI	RRMS (n = 289) of which 94 developed new BHs	37.4 (9.3)	64 (68%)	5.03 (4.8)	2.3 (0.97)	Brain MRI at months 0, 2, and 4; then monthly from month 7 to 12. All new (considering a two-month interval) BHs on axial MRIs were included in the analysisMonth 12: categorization of lesions as persistent or transient BHs (by one rater)	1.5 Tesla3 mm	Cronbachs’ alpha = 0.9Groups were masked to ratersIntra-rater agreement for the degree of hypointensity: 0.96	PBHs were more likely to be closer to the SVZ. Lesion size, ring contrast enhancement, and shorter normalized LV-distance could predict the 12-month BH persistence, with size being the strongest predictor

NR, not reported; PPMS, primary progressive multiple sclerosis; SPMS, secondary progressive multiple sclerosis; RRMS, relapsing–remitting multiple sclerosis, SMT, Spherical Mean Technique; INTRA, Neurite Signal fraction; EXTRATRANS, extraneurite transverse diffusivity; EXTRA-MD, extraneurite mean diffusivity; HC, healthy controls; NA-SVZ, normal-appearing subventricular zone; EDSS, Expanded Disability Status Scale; BHs, black holes; PBHs, persistent black holes.

In a multicenter, placebo-controlled phase II trial, authors analyzed the MRIs of 289 RRMS patients and investigated the relationship between lesion-to-ventricle (LV) distance and persistence of new black holes (BHs) (Papadopoulou et al., 2014). Authors found that BHs located close to SVZ were even more likely to persist over time than BHs located more distal to the ventricle wall, although without reaching statistical significance.

Postmortem studies

In their study, Nait-Oumesmar et al investigated the central body of the SVZ, derived from postmortem brain tissues of patients with MS (n = 17), and compared it with that of non-neurological controls (n = 5) (Nait-Oumesmar et al., 2007). Authors found evidence of high expression of GFAP in the SVZ and documented that the activation of SVZ in patients with MS contributes to the generation of PSA-NCAM progenitors in the ependymal–stem cell region. In particular, the number of PSA-NCAM progenitors was higher in lesions proximal to the SVZ compared with those located moderately (striatum) or far-remote (cortex, two blocks away) from the SVZ, which in association with the existence of progenitors with bipolar morphology indicates the migration along or away from the SVZ. The expression of early markers, including Sox9, Sox10, and Olig2 by PSA-NCAM progenitors suggested an activation of gliogenesis in the SVZ in patients with MS (Chang et al., 2002). Furthermore, early progenitors were found in periventricular MS lesions and were more abundant in active and chronic active lesions, where they could give rise to oligodendrocyte precursors, compared with chronic silent lesions, shadow plaques, or normal-appearing white matter (NAWM).

The expression profile of the low-affinity neutrophin receptor, p75^NTR, within the brains of patients with MS compared with normal brains was also investigated (Petratos et al., 2004). Although no evidence of expression of this receptor by mature oligodendrocytes was demonstrated within MS brains, the presence of p75^NTR was detected on a subgroup of NG2-positive oligodendroglial progenitors in a periventricular plaque in one MS sample and within the SVZ of this sample. These data indicate that the expression of this receptor, which can occur within SVZ, can be altered in response to periventricular demyelination. In an autopsy study of nine patients with MS and four controls without neurological disease, the authors documented the role of SVZ as one source of neoneurogenesis in MS brains (Chang et al., 2008). In particular, in the SVZ distant to chronic demyelinated lesions, neuronal densities were increased along with the activation of microglia and significant increase of mature and immature neurons.

In a patient with Marburg variant MS, the authors demonstrated lack of neurogenesis, even in very early stages of the disease, contrary to what is expected in acute brain lesions (Oreja-Guevara et al., 2017). In particular, morphology analysis of the SVZ of the lateral ventricle of a postmortem tissue sample showed that hypocellular and astrocytic layers were thicker compared with those of a control. Interestingly, markers of proliferation (Ki-67) and intermediate precursors (NG2) were decreased, and expression of the markers GFAPδ, SOX2, and PAX6 was also decreased.

Liu et al. investigated the expression of stathmin, a developmentally regulated tubulin-binding protein, in the brain of MS patients (n = 10) compared with that of controls with a history of temporal epilepsy (n = 4) and no neurological disease (n = 4) (Liu et al., 2005). In the brain autopsies of patients with MS, immunoreactivity of stathmin in the SVZ, was higher, confirmed by western blot analysis of protein lysates, and was associated with demyelination, extensive remyelination, and “shadow” plaques in the context of an inflammatory component.

Wang et al. investigated the role of Shh pathway signaling in the SVZ during inflammation, using brain tissues of MS patients, and showed that this pathway is upregulated by hypertrophic astroglia in correlation with enhanced GFAP expression during early inflammation in active lesions of MS (Wang et al., 2008). Surprisingly, Shh expression was higher at the border of the lesions and the NAWM adjacent to lesions and less at the core of the lesions. However, expression of Gli1 was significantly decreased in chronic active and inactive lesions.

James et al. analyzed human postmortem brain tissues of patients with MS (n = 7) and controls (n = 8) with immunohistochemistry and showed that Gal-3 was upregulated in periventricular lesions in patients with MS, especially in lesions delineated by the loss of proteolipid protein (PLP) immunoreactivity (James et al., 2016). Authors suggested that Gal-3 expression may modify SVZ neurogenic niche-mediated repair of myelin. Postmortem studies are presented in Table 4.

Table 4.

Post-Mortem Studies of Subventricular Zone

	Objective	Patients’ characteristics	Age, mean (SD) or median (IQR)	Female sex, n (%)	Disease duration in years, mean (SD)	EDSS, mean (SD)	Methodology	Main results
	Objective	Number	Age, mean (SD) or median (IQR)	Female sex, n (%)	Disease duration in years, mean (SD)	EDSS, mean (SD)	Methodology	Main results
Chang et al., 2002	To investigate the frequency distribution and configuration of oligodendrocytes in chronic MS lesions and determine whether these factors limit remyelination	n = 10 (MS patients)	55 (8.7)	4 (40%)	17.4 (13.5)	8 (1.2)	Immunohistochemical analysis; Confocal microscopy; Quantification of premyelinating oligodendrocytes	Early progenitors were found in periventricular MS lesions and were more abundant in active and chronic active lesions, where they could give rise to oligodendrocyte precursors, compared with chronic silent lesions, shadow plaques, or NAWM.
Liu et al., 2005	To investigate the expression of stathmin in conditions of myelin dysfunction	n = 10	NR		NR	NR	Immunohistochemistry; Stathmin identification in the C8a fraction isolated from myelin preparation of MS and control brains; western blots and slot blot quantitation; Transfection of myc-tagged stathmin in cultured oligodendrocyte progenitors; Effect of increased levels of stathmin on cell death induced by glucose deprivation	Increased immunoreactivity of stathmin in the SVZ from brains of MS patients was confirmed by western blot analysis of protein lysates and associated with demyelination, extensive remyelination, and “shadow” plaques in the context of an inflammatory component. In the differentiation process, sustained stathmin levels were linked to enhanced apoptoptic susceptibility.
Chang et al., 2008	To investigate subcortical white matter in MS lesions	n = 9SPMS (n = 7)PPMS (n = 1)RRMS (n = 1)	56 (10.1)	4 (44%)	22 (14.1)	8 (1.3)	Macroscopical identification of 66 demyelinated regions in the subcortical white matter; Characterization as active or chronic Immunohistochemical analysis and immunostaining with specific antibodies; Microscopy; Quantification of MAP2-positive and NeuN-positive neurons; Electron microscopy; Immunohistochemistry	Increased number of NeuN-positive neurons with phenotypic features of neuronal progenitor cells in the SVZs close to demyelinated regions in comparison to NAWM
Oreja-Guevara et al., 2017	To analyze neurogenesis in a male patient with Marburg variant MS	MS, Marburg variant (n = 1)	27	0	20 days	Rapid disease progression leading to death 20 days after symptom onset	Histologic and immunohistochemical study of neurogenic niches with quantification of GFAPα, GFAPδ, MHCII, Iba1, and MBP; Evaluation of markers against Ki-67, PCNA, Musashi-1, and SOX2 in the SVZ	Low levels of stem cell markers GFAPδ, SOX2, and PAX6, as well as proliferation (Ki-67) and intermediate precursors (NG2) markers, signifying inhibition of neurogenesis early on in the disease course
Nait-Oumesmar, 2007	To examine brains of MS patients’ postmortem regarding generation of glial cell progenitors (PSA-NCAM⁺) in SVZ and lesion tissues with possible reparatory role in the demyelination process	n = 17PPMS (n = 3)SPMS (n = 12)RRMS (n = 1)RPMS (n = 1)	57 (11.2)	NR	28 (8–39)	NR	Histological and immunohistochemical study. PSA-NCAM⁺/GFAP^- cells were quantified in MS lesions	Increase PSA-NCAM⁺ and GFAP⁺ cells in MS compared with controls (with expression of Sox9⁺ mainly). Increased PSA-NCAM⁺ progenitors in active and chronic active lesions (especially periventricular) indicating gliogenesis activation, and mobilization in the SVZ of patients with MS
Petratos et al., 2004	To assess the expression of the low- affinity neurotrophin receptor, p75^NTR, a possible regulator of precursor cell repopulation, in MS patients and controls	n = 8Chronic MS (n = 5)Acute MS (n = 3)	41 (8.6)	6 (75%)	7.2 (6.9)	NR	Histopathological analysis; Immunohistochemistry with anti-p75; In situ cell death detection;Stereological analysis	No p75^NTR expression was demonstrated in mature oligodendrocytes within MS brains. However, the receptor was present on NG2-positive oligodendroglial progenitors in a periventricular plaque in one MS sample and within the SVZ of this sample.
Wang et al., 2008	To study the regulation of inflammatory injury of NSCs’ intrinsic properties through investigation of the role of the sonic hedgehog (Shh)-Gli1 pathway and its association with inflammatory cytokines.	n = 17Active MSS (n = 3)Chronic active MS (n = 9)Inactive MS (n = 5)	47.8 (13.3)	17 (59%)	NR	NR	Primary neural stem cell and astroglia isolation and culture; NSC differentiation; Gli1 gene silencing	Hypertrophic astroglia upregulate the Shh pathway, in correlation with enhanced GFAP expression during early inflammation in active lesions of MS. Shh expression was higher at the border of the lesions and the NAWM adjacent to lesions and less at the core of the lesions. However, expression of Gli1 was significantly decreased in chronic active and inactive lesions.
James et al., 2016	To study the role of galectin-3, a proinflammatory protein, in SVZ-specific cellular proliferation in the context of MS-induced inflammation	n = 7 (cases with active inflammatory demyelination in periventricular regions)	43.4 (5.4)	5 (71%)	NR	NR	Immunohistochemistry; Cell quantification and analysis using Aperio image analysis system	Gal-3 was upregulated in periventricular lesions in MS patients, especially in lesions with no proteolipid protein (PLP) immunoreactivity. Results suggesting that Gal-3 expression may modify SVZ-mediated repair of myelin.
Tepavčević et al., 2011	To examine whether MS-like pathology affects SVZ constitutive neurogenesis and olfaction	n = 3SPMS (n = 2)RRMS (n = 1)	52 (8.9)	NR	18.91 (6.63)	NR	Histological assessment; Immunostaining	Decreased neuroblast density and neurogenesis in MS brains compared with controls, suggesting functional alteration of adult NSCs due to inflammation that may contribute to olfactory dysfunction in MS patients

NR, not reported; PPMS, primary progressive multiple sclerosis; SPMS, secondary progressive multiple sclerosis; RRMS, relapsing–remitting multiple sclerosis; EDSS, Expanded Disability Status Scale; NAWM, normal-appearing white matter; MAP-2, microtubule-associated protein 2; NeuN, neuronal nuclear antigen; GFAP, glial fibrillary acidic protein; MHC, major histocompatibility complex; Iba1, Ionized calcium-binding adaptor molecule 1; MBP, myelin basic protein; PCNA, Proliferating cell nuclear antigen; SOX2, Sex-determining region Y-related HMG box; PSA-NCAM, polysialic acid–neural cell adhesion molecule; NG2, a chondroitin sulfate proteoglycan; Gal-3, galectin-3.

Discussion

This study aimed to systematically review the evidence on mechanisms and phenomena associated with SVZ dysfunction/impairment in MS models of animals, human subjects, and postmortem species. Overall, data derived from animal studies yield the significance of SVZ in the neurogenesis and oligodendrocyte maturation, which takes place in the context of demyelination and remyelination. The role of SVZ in myelin repair was explored in seven studies indirectly through the role of NSCs derived from this area both in chronic and acute stages of the disease with contradictory results (Payne et al., 2012). During the acute stage of the disease, NSCs derived from SVZ proliferate and differentiate into OLs and then migrate to demyelinating plaques, and even in areas distant to SVZ (Sherafat et al., 2012), as seen in Figure 2. Starossom et al. found that, during the acute stage of the disease, SVZ microglia act as mediators of white matter damage or repair of myelin and organize the networks, which support the NSC’s niche (Starossom et al., 2011).

FIG. 2.

A schematic representation of peripheral-to-central cross talk between the subventricular zone and peripheral sites of potential inflammation. Commensal microbiota in the gut and airways interact with immune cells and provide a tonic, basal inflammatory response lies within homeostatic limits. This response may fluctuate as commensal populations shift, or pathogenic organisms or other inflammatory stimuli are introduced. Acute inflammation may thus result in a shift from homeostatic, tonic signals to the subventricular zone (SVZ) to signals that if left unmitigated, will cause neuroinflammation. Prolonged exposure to peripheral inflammation and neuroinflammation will eventually create a noxious environment for neural and oligodendroglial progenitors, hampering neoneurogenesis and oligodendrogenesis, respectively. This outside-in crosstalk will progressively install a local proinflammatory environment in the SVZ.

Pathways involved in the proliferation and migration of NSCs include the upregulation of CXCR4 signaling (Banisadr et al., 2011) and the inhibition of Shh-Gli1 pathway during chronic active or inactive lesions (Samanta et al., 2015; Wang et al., 2008). However, the Shh-Gli1 pathway is upregulated during early inflammation by hypertrophic astroglia. Current data support the role of Epstein–Barr virus (EBV) latent membrane protein 2A (LMP2A) in the activation of Shh pathway in gastric cancer cells, leading to decrease of HLA Class IA (Deb Pal and Banerjee, 2015). However, during the chronic stage of the disease, evidence support NSC’s niche dysfunction (Payne et al., 2012), although this phenomenon is reversible, through inhibition of microglial activation (Rasmussen et al., 2011), denoting the importance of niche microenvironment (Starossom et al., 2011). James et al. discussed on the role of Gal-3 in modulating the immune response in the SVZ niche in animal models with MS and in brain tissues of patients with MS (James et al., 2016). Rasmussen et al. (2016) studied a cohort of Systemic Lupus Erythematosus (SLE) and demonstrated a positive association between ongoing/recently active EBV infection, positivity for anti-extractable nuclear antigens (anti-ENAs), and increased plasma Gal-3-binding protein (G3BP) concentrations/type I IFN activity. The increased plasma G3BP concentrations are associated with loss of SVZ proliferation and decreased number of progenitors in the CC, which is positively associated with ongoing or recently active EBV infection. This phenomenon is observed in the chronic stage of the disease, indicating an association between EBV infection and progression of the disease.

Evidence from postmortem studies support the role of SVZ in the neoneurogenesis and oligodendrogenesis in patients with MS. Oligodendrogenesis is mostly observed in active and chronic active lesions close to SVZ (Chang et al., 2008; Chang et al., 2002; Nait-Oumesmar et al., 2007) but not in chronic silent lesions or shadow plaques, even in more distant areas. This observation may explain the diminished myelin repair during the chronic stage of the disease. Cellerino et al. showed that microstructural damages of SVZ mostly occur during the chronic stage of the disease, possibly accounting for diminished myelin repair efficiency during the progressive phases of the disease.

Our results should be interpreted with some caution given the limitations of our design. First, although we divided the study into three categories based on the study population, there was a great deal of heterogeneity between the studies used. In particular, for data extracted from animal studies, a great variety of techniques were described and different animal models were used. Second, we have only searched for publication in MEDLINE, SCOPUS, ProQuest, and Google Scholar and, therefore, articles that are indexed exclusively in other databases are not represented herein. Finally, there were no restrictions in date of publication applied in this review. This was a deliberate decision made to review the full range of literature pertinent to the topic in question.

Conclusion

Our systematic review attempted to synthesize evidence on the role of the SVZ, the site for neoneurogenesis and oligodendrogenesis in MS. Defects in oligodendrogenesis specifically would translate in a reduced capacity of remyelination, a defect that can readily drive and shape the end-phenotype and disease course in MS.

Despite its obvious importance, SVZ is relatively underexplored in the literature, as our systematic review emphasized; its importance, however, is evident from both animal and human studies reviewed herein and indicates that remyelination defects may exacerbate the disruption of the SVZ microenvironment secondary to dysregulated inflammation and potentially, infection. This systematic review of the literature outlines key molecular players, such as the Gli-Shh pathway that may be druggable and relevant to remyelination approaches in demyelinating disease.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any studies with human participants or animal models performed by any of the authors. Therefore, ethics review was not required.

Footnotes

Authors’ Contributions

A.L.: Conceptualization or design of the work (lead); data collection (lead); data analysis (lead); data interpretation (lead); writing––original draft (lead); (lead); and critical revision of the article (lead). V.-S. T.: Conceptualization or design of the work (lead); data collection (lead); data analysis (lead); data interpretation (lead); writing––original draft (lead); and critical revision of the article (lead). A.A.: critical revision of the article (supporting). P.Z.: critical revision of the article (supporting). C.A.: critical revision of the article (supporting). N.G.: critical revision of the article (supporting). G.M.H.: critical revision of the article (supporting). G.V.: Conceptualization or design of the work (equal); and critical revision of the article (lead).

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding or sponsorship was received for this study or publication of this article.

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