Multiple sclerosis is a devastating demyelinating disease of the central nervous system (CNS) in which endogenous remyelination, and thus recovery, often fails. Although the cuprizone mouse model allowed elucidation of many molecular factors governing remyelination, currently very little is known about the spatial origin of the oligodendrocyte progenitor cells that initiate remyelination in this model. Therefore, we here investigated in this model whether subventricular zone (SVZ) neural stem/progenitor cells (NSPCs) contribute to remyelination of the splenium following cuprizone-induced demyelination. Experimentally, from the day of in situ NSPC labeling, C57BL/6J mice were fed a 0.2% cuprizone diet during a 4-week period and then left to recover on a normal diet for 8weeks. Two in situ labeling strategies were employed: (i) NSPCs were labeled by intraventricular injection of micron-sized iron oxide particles and then followed up longitudinally by means of magnetic resonance imaging (MRI), and (ii) SVZ NSPCs were transduced with a lentiviral vector encoding the eGFP and Luciferase reporter proteins for longitudinal monitoring by means of in vivo bioluminescence imaging (BLI). In contrast to preceding suggestions, no migration of SVZ NSPC towards the demyelinated splenium was observed using both MRI and BLI, and further validated by histological analysis, thereby demonstrating that SVZ NSPCs are unable to contribute directly to remyelination of the splenium in the cuprizone model. Interestingly, using longitudinal BLI analysis and confirmed by histological analysis, an increased migration of SVZ NSPC-derived neuroblasts towards the olfactory bulb was observed following cuprizone treatment, indicative for a potential link between CNS inflammation and increased neurogenesis.
Keywords: AP; APC/CC1; BG; BLI; Bioluminescence imaging; CC; CNS; Cuprizone; DV; EAE; EWD; GE; GFAP; IBA1; LVv; La; MBP; MPIO; MRI; MS; Magnetic resonance imaging; Migration; NSPC; NeuN; Neural stem cell; OB; PBS; PC; PLL; RF; RMS; ROI; Remyelination; SVZ; VOI; adenomatous polyposis coli; antero-posterior; background; bioluminescence imaging; central nervous system; corpus callosum; dorso-ventral; eGFP; enhanced green fluorescent protein; error weighted difference; experimental auto-immune encephalomyelitis; fLuc; firefly luciferase; glial fibrillary acidic protein; gradient echo; ionized calcium binding adaptor molecule; lateral; lentiviral vector; mIPs; magnetic resonance imaging; micron-sized iron oxide particles; minimum intensity projections; multiple sclerosis; myelin basic protein; neural stem progenitor cell; neuronal nuclear antigen; olfactory bulb; p.i.; p75 neurotrophin receptor; p75NTR; phosphate buffered saline; poly-l-lysine; positive control; post-injection; radio-frequency; region of interest; rostral migratory stream; sCC; splenium of the corpus callosum; subventricular zone; volume of interest.
© 2013.