Experimental Demyelination in Adult Rat Optic Chiasm and Nerve Mobilizes Endogenous Neural Stem Cells from the Lateral Subventricular Zone and Rostral Migratory Stream

Mozafari S *, Sherafat M.A , Javan M , Mirnajafi-Zadeh J , Tiraihi T ,


Objective: Adult mammalian brain contains multipotent neural stem cells reside mainly in germinal zones including subventricular zone (SVZ) of lateral ventricle and rostral migratory stream (RMS). Identifying cells with the capacity to generate oligodendrocytes in the adult CNS and assessment of their migrating potential would help in the development of strategies to promote endogenous remyelination. Regarding to vulnerability of optic apparatus, particularly optic chiasm and nerves in Multiple Sclerosis, here, it was tried to determine whether endogenous neural stem cells from these germinal zones are able to mobilize in response to the experimental local demyelination in adult rat optic chiasm and nerves? Materials and Methods: We profited from an improved demyelination model which is able to built-in rat optic chiasm and nerves simultaneously following stereotaxic microinjection of lysolecithin (LPC) into the chiasm without undesirable distribution. Histological and functional verifications of the model and the repair assessment were accomplished using special myelin staining and visual evoked potential recording. Gene expression level for MBP, Olig2 and GFAP; consequently as mature oligodendrocytes activity, reactive oligodendrocyte precursor cells and astrocytes activity, were assessed at the site of lesion at 2, 7, 14 and 28 days post induction (dpi). Endogenous adult stem cell tracing was performed using intraperitoneal administration of BrdU prior to the gliotoxin injection and assessment of antigenisity against Nestin, immunohistochemicaly. Results: Demyelination was considerable in days 7 and 14 and an incomplete remyelination occurred in 28 dpi. MBP gene expression was decreased significantly on day 7 post induction, but Olig2 and GFAP gene expression were increased at this time-point. These changes, then, were slowly reversed at days 14 and 28. Because in control animals BrdU labeled cells were restricted to the SVZ and RMS, their presence in structures other than the SVZ and RMS implies that they originate from the SVZ or RMS. Two days post induction, number of BrdU+ cells in SVZ and RMS were increased and 7 dpi, these cells were left SVZ and RMS and located in the brain parenchyma with a cell gradient in which more number of cells placed near the SVZ and RMS and distributed toward the demyelinated area. Nestin, a neural stem cell marker was up-regulated at the site of injury and also in walls of lateral ventricle at 2 dpi and reached to a maximum level at 7 dpi which then was sustained in tissue with lower expression by time. Double staining studies on lateral ventricle walls on day 7 post induction was revealed that only a few Nestin+ cells were also BrdU+. Conclusion: SVZ and RMS endogenous adult neural stem cells are able to be recruited by existence of experimental demyelination even in the adult white matters like optic chiasm and nerves where locate far from the lateral ventricles and are commonly affected by MS.