Research: Experimental Remyelination

EpubWhitman et al. Olig1 function is required for remyelination potential of transplanted neural progenitor cells in a model of viral-induced demyelination.Exp Neurol. 2012 Mar

MS is a chronic inflammatory disease of the central nervous system (CNS) resulting in cumulative neurologic deficits associated with progressive myelin loss. 

These investigators have previously shown that transplantation of neural progenitor cells (NPCs) into mice persistently infected with the JHM strain of mouse hepatitis virus (JHMV) results in enhanced differentiation into oligodendrocyte progenitor cells (OPCs) that is associated with remyelination and axonal sparing. 

The current study examines the contributions of the transcription factor Olig1 on NPC differentiation and remyelination. Under defined conditions, NPCs preferentially differentiate into oligodendroglia whereas NPCs isolated from Olig1-deficient (Olig1-/-) mice exhibit enhanced differentiation into astrocytes. Transplantation of Olig1-/- and Olig1+/+ NPCs into JHMV-infected mice resulted in similar cell survival, proliferation, and selective migration to areas of demyelination. However, only recipients of wild type NPCs exhibited extensive remyelination compared to mice receiving Olig1-/- NPCs. In vivo characterization of NPCs revealed that Olig1+/+ NPCs preferentially differentiated into NG2-positive OPCs and formed processes expressing myelin basic protein that encircled axons. In contrast, the majority of transplanted Olig1-/- NPCs differentiated into GFAP-positive cells consistent with the astrocyte lineage. 

These results indicate that exogenous NPCs contribute to improved clinical and histological (under the microscope) outcome and this is associated with remyelination by this donor population. Further, these findings reveal that Olig1 function is required for the remyelination potential of NPCs after transplant, through specification and/or maintenance of oligodendroglial identity.

Axon (nerve process) wrapped in layers of myelin.

“Immature oligodendrocytes can mature into oligodendrocytes or can become astrocytes. This study shows that Olig1 a factor that drives the production of oligodendrocyte-related genes help drive this process to produce oligodendrocytes that can then repair the myelin. This study using mice deficient in this process, can show that Olig1 is central to the remyelination process. So further studies leading towards the understanding of how to promote remyelination.”

Sher F, Amor S, Gerritsen W, Baker D, Jackson SL, Boddeke E, Copray S. Intraventricularly injected Olig2-NSCs attenuate established relapsing-remitting EAE in mice.Cell Transplant. 2012 Mar 28. [Epub ahead of print 

In multiple sclerosis (MS), a chronic inflammatory relapsing demyelinating disease, failure to control or repair damage leads to progressive neurological dysfunction and neurodegeneration. Implantation of neural stem cells (NSCs) has been shown to promote repair and functional recovery in the acute experimental autoimmune encephalomyelitis (EAE) animal model for MS; the major therapeutic mechanism of these NSCs appeared to be immune regulation. In the present study, we examined the efficacy of intraventricularly injected NSCs in chronic relapsing experimental autoimmune encephalomyelitis (CREAE), the animal disease model which is widely accepted to mimic most closely recurrent inflammatory demyelination lesions as observed in relapsing-remitting MS. In addition, we assessed whether priming these NSCs to become oligodendrocyte precursor cells (OPCs) by transient overexpression of Olig2 would further promote functional recovery, e.g. by contributing to actual remyelination.Upon injection at the onset of the acute phase or the relapse phase of CREAE, NSCs as well as Olig2-NSCs directly migrated towards active lesions in the spinal cord as visualized by in vivo bioluminescence and biofluorescence imaging and once in the spinal cord the majority of Olig2-NSCs, in contrast to NSCs, differentiated into OPCs. The survival of Olig2-NSCs was significantly higher than that of injected control NSCs, which remained undifferentiated. Nevertheless both Olig2-NSCs and NSC significantly reduced the clinical signs of acute and relapsing disease, and, in case of Olig2-NSCs, even completely abrogated relapsing disease when administered early after onset of acute disease. We provide the first evidence that NSCS and in particular NSC-derived OPCs (Olig2-NSCs) ameliorate established chronic relapsing EAE in mice. Our experimental data in established neurological disease in mice indicates that such therapy may be effective in relapsing-remitting MS preventing chronic progressive disease.

Neural stem cells could inhibit the immune response as has been shown previously. However it must be said that there are far easy and more effective ways of inhibiting the immune response than by using stem cells and if this is all that stem cells are doing then the stratetgy needs to be changed. This study shows that neural stem cells did not do much in terms of becoming oligodendrocyctes, unless the get an extra signal from boosted Olig-2 activity to differentiate and mature. 

CoI. This work is from Team G

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