title: Intraventricularly injected Olig2-NSCs attenuate established relapsing-remitting EAE in mice.
abstract: 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 that 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, for example, 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 toward 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 indicate that such therapy may be effective in relapsing-remitting MS preventing chronic progressive disease.
authors.affiliation: Department of Neuroscience, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Falak
authors.initials: F
authors.lastname: Sher
authors.forename: Sandra
authors.initials: S
authors.lastname: Amor
authors.forename: Wouter
authors.initials: W
authors.lastname: Gerritsen
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Jackson
authors.forename: Erik
authors.initials: E
authors.lastname: Boddeke
authors.forename: Sjef
authors.initials: S
authors.lastname: Copray
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000008:administration & dosage / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000502:physiology; D003711:Demyelinating Diseases / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000628:therapy*; D005260:Female; D007276:Injections, Intraventricular; D051379:Mice; D009103:Multiple Sclerosis / Q000473:pathology / Q000628:therapy*; D009186:Myelin Sheath / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000096:biosynthesis*; D058953:Neural Stem Cells / Q000378:metabolism / Q000637:transplantation*; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000378:metabolism / Q000637:transplantation*; D033581:Stem Cell Transplantation / Q000379:methods*; D014162:Transfection
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; C512773:Olig2 protein, mouse