Multimodal imaging of subventricular zone neural stem/progenitor cells in the cuprizone mouse model reveals increased neurogenic potential for the olfactory bulb pathway, but no contribution to remyelination of the corpus callosum

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.

[1]  Daniel H. Turnbull,et al.  In vivo MRI of neural cell migration dynamics in the mouse brain , 2010, NeuroImage.

[2]  Richard Reynolds,et al.  NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS , 2003, Molecular and Cellular Neuroscience.

[3]  Herman Goossens,et al.  Cell Type-Associated Differences in Migration, Survival, and Immunogenicity following Grafting in CNS Tissue , 2012, Cell transplantation.

[4]  Daniel A. Lim,et al.  Subventricular Zone Astrocytes Are Neural Stem Cells in the Adult Mammalian Brain , 1999, Cell.

[5]  Jian Yang,et al.  In vivo MRI of endogenous stem/progenitor cell migration from subventricular zone in normal and injured developing brains , 2009, NeuroImage.

[6]  Zeger Debyser,et al.  Quantitative evaluation of MRI-based tracking of ferritin-labeled endogenous neural stem cell progeny in rodent brain , 2012, NeuroImage.

[7]  Oscar Gonzalez-Perez,et al.  Origin of Oligodendrocytes in the Subventricular Zone of the Adult Brain , 2006, The Journal of Neuroscience.

[8]  Uwe Himmelreich,et al.  In situ labeling and imaging of endogenous neural stem cell proliferation and migration. , 2012, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[9]  Alain Pitiot,et al.  A multimodal, multidimensional atlas of the C57BL/6J mouse brain , 2004, Journal of anatomy.

[10]  Guy Marchal,et al.  Multimodality image registration by maximization of mutual information , 1997, IEEE Transactions on Medical Imaging.

[11]  M. Taniike,et al.  Mature oligodendrocyte apoptosis precedes IGF‐1 production and oligodendrocyte progenitor accumulation and differentiation during demyelination/remyelination , 2000, Journal of neuroscience research.

[12]  Ruth Vreys,et al.  In Vivo Monitoring of Adult Neurogenesis in Health and Disease , 2011, Front. Neurosci..

[13]  L. P. Chen,et al.  Regulation of Olig2 during astroglial differentiation in the subventricular zone of a cuprizone-induced demyelination mouse model , 2012, Neuroscience.

[14]  P. Walczak,et al.  Applicability and limitations of MR tracking of neural stem cells with asymmetric cell division and rapid turnover: The case of the Shiverer dysmyelinated mouse brain , 2007, Magnetic resonance in medicine.

[15]  J. García-Verdugo,et al.  Immunological regulation of neurogenic niches in the adult brain , 2012, Neuroscience.

[16]  Annemarie van der Linden,et al.  MRI visualization of endogenous neural progenitor cell migration along the RMS in the adult mouse brain: Validation of various MPIO labeling strategies , 2010, NeuroImage.

[17]  Robin J. M. Franklin,et al.  Remyelination in the CNS: from biology to therapy , 2008, Nature Reviews Neuroscience.

[18]  Mark F. Lythgoe,et al.  In vivo magnetic resonance imaging of endogenous neuroblasts labelled with a ferumoxide–polycation complex , 2009, NeuroImage.

[19]  Bostjan Likar,et al.  Retrospective Correction of MR Intensity Inhomogeneity by Information Minimization , 2000, MICCAI.

[20]  Eduardo Soto,et al.  Cuprizone‐induced demyelination in CNP::GFP transgenic mice , 2010, The Journal of comparative neurology.

[21]  Zeger Debyser,et al.  Characterization of lentiviral vector-mediated gene transfer in adult mouse brain. , 2002, Human gene therapy.

[22]  Anne Baron-Van Evercooren,et al.  Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Dustin Scheinost,et al.  Serial monitoring of endogenous neuroblast migration by cellular MRI , 2011, NeuroImage.

[24]  Alan P. Koretsky,et al.  Magnetic resonance imaging of the migration of neuronal precursors generated in the adult rodent brain , 2006, NeuroImage.

[25]  Trevor J Kilpatrick,et al.  Expression of the low‐affinity neurotrophin receptor, p75NTR, is upregulated by oligodendroglial progenitors adjacent to the subventricular zone in response to demyelination , 2004, Glia.

[26]  Martin Stangel,et al.  De- and remyelination in the CNS white and grey matter induced by cuprizone: the old, the new, and the unexpected. , 2011, Histology and histopathology.

[27]  Sjef Copray,et al.  The cuprizone animal model: new insights into an old story , 2009, Acta Neuropathologica.

[28]  Sebastien Couillard-Despres,et al.  In vivo imaging of adult neurogenesis , 2011, The European journal of neuroscience.

[29]  D. Rowitch,et al.  CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. , 2010, Cell stem cell.

[30]  Erik M Shapiro,et al.  Enhanced magnetic cell labeling efficiency using –NH2 coated MPIOs , 2011, Magnetic resonance in medicine.

[31]  Zeger Debyser,et al.  Lentiviral vectors mediate efficient and stable gene transfer in adult neural stem cells in vivo. , 2006, Human gene therapy.

[32]  Alan P. Koretsky,et al.  In vivo labeling of adult neural progenitors for MRI with micron sized particles of iron oxide: Quantification of labeled cell phenotype , 2009, NeuroImage.

[33]  Zeger Debyser,et al.  Noninvasive and Quantitative Monitoring of Adult Neuronal Stem Cell Migration in Mouse Brain Using Bioluminescence Imaging , 2008, Stem cells.

[34]  Herman Goossens,et al.  Clinical Potential of Intravenous Neural Stem Cell Delivery for Treatment of Neuroinflammatory Disease in Mice? , 2011, Cell transplantation.

[35]  U Himmelreich,et al.  Evaluation of the specificity and sensitivity of ferritin as an MRI reporter gene in the mouse brain using lentiviral and adeno-associated viral vectors , 2011, Gene Therapy.

[36]  Frederik Barkhof,et al.  Remyelinated lesions in multiple sclerosis: magnetic resonance image appearance. , 2003, Archives of neurology.

[37]  Dominik S. Meier,et al.  Time-series analysis of MRI intensity patterns in multiple sclerosis , 2003, NeuroImage.