Limited remyelination in Theiler's murine encephalomyelitis due to insufficient oligodendroglial differentiation of nerve/glial antigen 2 (NG2)-positive putative oligodendroglial progenitor cells

Abstract

Limited remyelination in Theiler's murine encephalomyelitis due to insufficient oligodendroglial differentiation of nerve/glial antigen 2 (NG2)-positive putative oligodendroglial progenitor cellsAims: Limited remyelination is a key feature of demyelinating Theiler's murine encephalomyelitis (TME). It is hypothesized that a dysregulation of differentiation of oligodendroglial progenitor cells (OPCs) represents the main cause of insufficient regeneration in this model of multiple sclerosis. Methods: TME virus (TMEV)-infected SJL/J mice were evaluated by footprint analysis, light and electron microscopy, immunohistology, confocal immunofluorescence and RT-qPCR at multiple time points ranging from 1 h to 196 days post infection (dpi). Results: Footprint analysis revealed a significantly decreased stride length at 147 and 196 dpi. Demyelination progressively increased from 14 towards 196 dpi. A mild amount of remyelination was detected at 147 and 196 dpi. Early onset axonal injury was detected from 14 dpi on. TMEV RNA was detectable throughout the observation period and markedly increased between 7 and 28 dpi. Intralesional nerve/ glial antigen 2 (NG2)-positive OPCs were temporarily increased between 28 and 98 dpi. Similarly, a transient upregulation of NG2 and platelet-derived growth factor a-receptor mRNA was noticed. In contrast, intralesional 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase)-positive oligodendrocytes were decreased between 56 and 196 dpi. Although CNPase mRNA remained unchanged, myelin basic protein mRNA and especially its exon 2 containing splice variants were decreased. Glial fibrillary acidic protein (GFAP)-positive astrocytes and GFAP mRNA were increased in the late phase of TME. A mildly increased colocalization of both NG2/CNPase and NG2/ GFAP was revealed at 196 dpi. Conclusions: Summarized, the present results indicated a dysregulation of OPC maturation as the main cause for the delayed and limited remyelination in TME. A shift of OPC differentiation from oligodendroglial towards astrocytic differentiation is postulated.

Periventricular Demyelination and Axonal Pathology Is Associated with Subependymal Virus Spread in a Murine Model for Multiple Sclerosis

“…The lack of detectable TMEV antigen and RNA in the periventricular region of investigated SJL/J mice during the late chronic disease phase is indicative of complete viral elimination without evidence of restricted infection. Accordingly, viral persistence with ongoing myelin degradation and impaired remyelination in the brain stem requires continuous viral replication as suggested for the spinal cord of TMEV-infected mice [11,50]. Recent studies showed that T cell-mediated immunity leads to viral elimination from the ependyma but not from the brain parenchyma in experimental attenuated lymphocytic choriomeningitis virus infection of mice due to regionally different efficacies of immune responses within the CNS [51].…”

“…Each laser line was scanned separately for individual excitation of the dyes, and data sets were finally merged and analyzed employing the Leica application suite advanced fluorescence (LAS AF; Leica, Wetzlar, Germany). The different cell types were identified according to their morphological characteristics and antigen expression [11]. …”

“…Further, following injury, the expression of phosphorylated neurofilament (p-NF) decreases and n-NF represents the dominating isoform [5,6,7,8]. Similarly, axonopathies as a consequence of dysregulated axonal transport mechanisms and impaired neurofilament phosphorylation can be observed in the spinal cord of TMEV-infected mice [8,9,10,11,12]. …”

Matrix metalloproteinase-12 deficiency ameliorates the clinical course and demyelination in Theiler’s murine encephalomyelitis

“…TME virus (TMEV) strains can be divided into two major groups: (1) the GDVII and FA strain, which produce an acute fatal polioencephalomyelitis, and (2) Theiler's original (TO) group, including the BeAn, Daniels (DA), and WW strains [16]. Intracerebral infection of susceptible mice with TMEV strains of the TO group induces a biphasic disease course consisting of an acute polioencephalitis followed by a chronic progressive leukomyelitis with demyelination, astrogliosis, and virus persistence in macrophages/microglia, astrocytes, and oligodendrocytes [16,54,66]. During TME, Mmp12 mRNA was prominently upregulated in the demyelinating phase of the disease days postinfection (dpi)], and MMP-12 protein was localized in intralesional microglia/macrophages and astrocytes [63].…”

A Sativex®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

“…Chronic demyelination in the TMEV model is accompanied by alterations in spinal cord ECM and astrogliosis (Haist et al, 2012) which in turn contribute to the failure in regeneration. Accordingly, limited remyelination in TMEV has been associated with insufficient oligodendroglial differentiation (Ulrich et al, 2008). While cannabinoids have been shown to improve remyelination (Arévalo-Martín et al, …”