Potential of Adult Endogenous Neural Stem/Progenitor Cells in the Spinal Cord to Contribute to Remyelination in Experimental Autoimmune Encephalomyelitis

Abstract

Demyelination and remyelination play pivotal roles in the pathological process of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), a well-established animal model of MS. Although increasing evidence shows that various stimuli can promote the activation/induction of endogenous neural stem/progenitor cells (NSPCs) in the central nervous system, the potential contributions of these cells to remyelination following inflammatory injury remain to be fully investigated. In the present study, using an adult mouse model of EAE induced by myelin oligodendrocyte glycoprotein (MOG) peptide, we investigated whether adult NSPCs in the spinal cord can lead to remyelination under inflammatory conditions. Immunohistochemistry showed that cells expressing the NSPC marker Nestin appeared after MOG peptide administration, predominantly at the sites of demyelination where abundant inflammatory cells had accumulated, whereas Nestin+ cells were rarely present in the spinal cord of PBS-treated control mice. In vitro, Nestin+ NSPCs obtained from EAE mice spinal cords could differentiate into multiple neural lineages, including neurons, astrocytes, and myelin-producing oligodendrocytes. Using the Cre–LoxP system, we established a mouse strain expressing yellow fluorescent protein (YFP) under the control of the Nestin promoter and investigated the expression patterns of YFP-expressing cells in the spinal cord after EAE induction. At the chronic phase of the disease, immunohistochemistry showed that YFP+ cells in the injured regions expressed markers for various neural lineages, including myelin-forming oligodendrocytes. These results show that adult endogenous NSPCs in the spinal cord can be subject to remyelination under inflammatory conditions, such as after EAE, suggesting that endogenous NSPCs represent a therapeutic target for MS treatment.

Early Reperfusion Following Ischemic Stroke Provides Beneficial Effects, Even After Lethal Ischemia with Mature Neural Cell Death

“…Neurosphere-like cell clusters were subjected to reverse transcription polymerase chain reaction (RT-PCR) 21 d after incubation (see below). Clusters were differentiated on poly- l -lysine-coated (0.05%) glass coverslips for 7 d in neurobasal medium (Invitrogen) containing bFGF, B-27 supplement (Invitrogen), and 2% fetal bovine serum as previously described [ 20 ]. The differentiated cell clusters were subjected to RT-PCR and immunohistochemistry using antibodies against Tuj1 (1:1000; mouse; Stemcell Technologies, Vancouver, BC, Canada), MAP-2 (1:1000, rabbit, Millipore), glial fibrillary acidic protein (GFAP) (1:1000, rabbit, Abcam), and myelin basic protein (MBP) (1:100, R&D systems), followed by Alexa Fluor 488- or 555-conjugated secondary antibodies (1:500; Molecular Probes).…”

“…Total RNA was extracted using an RNeasy Micro Kit (Qiagen, Hilden, Germany) as previously described [ 12 , 20 , 21 , 22 ]. In brief, total RNA was extracted from the differentiated cell clusters obtained after 90-min t-MCAO and p-MCAO.…”

How Long Are Reperfusion Therapies Beneficial for Patients after Stroke Onset? Lessons from Lethal Ischemia Following Early Reperfusion in a Mouse Model of Stroke

“…There is also increasing evidence showing that various types of stem cell populations such as neural stem/progenitor cells (NSPCs) reside in the central nervous system [ 86 , 87 ]. The precise origins and traits of stem cells that contribute to neural repair remain unclear; however, a growing body of evidence indicates that brain pericytes can behave as NSPC-like cells under pathological conditions such as those observed after ischemic stroke [ 21 , 22 , 62 ].…”

Promising Nanotechnology Approaches in Treatment of Autoimmune Diseases of Central Nervous System

“…However, increasing evidence shows that remyelination occurs in the MS/EAE [57][58][59][60]. In addition, recent studies showed that activated neural stem/progenitor cells around region sites contribute to remyelination [61,62]. Promoting remyelination, therefore, provides an additional line of defense against the axonal damage that follows the loss of myelin.…”