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Intracerebral transplantation of interleukin 13-producing mesenchymal stem cells limits microgliosis, oligodendrocyte loss and demyelination in the cuprizone mouse model

Le Blon, Debbie; Guglielmetti, Caroline; Hoornaert, Chloé; Quarta, Alessandra; Daans, Jasmijn; Dooley, Dearbhaile; Lemmens, Evi; Praet, Jelle; De Vocht, Nathalie; Reekmans, Kristien; Santermans, Eva; Hens, Niel; Goossens, Herman; Verhoye, Marleen; Van der Linden, Annemie; Berneman, Zwi; Hendrix, Sven; Ponsaerts, Peter

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  <dc:creator>Le Blon, Debbie</dc:creator>
  <dc:creator>Guglielmetti, Caroline</dc:creator>
  <dc:creator>Hoornaert, Chloé</dc:creator>
  <dc:creator>Quarta, Alessandra</dc:creator>
  <dc:creator>Daans, Jasmijn</dc:creator>
  <dc:creator>Dooley, Dearbhaile</dc:creator>
  <dc:creator>Lemmens, Evi</dc:creator>
  <dc:creator>Praet, Jelle</dc:creator>
  <dc:creator>De Vocht, Nathalie</dc:creator>
  <dc:creator>Reekmans, Kristien</dc:creator>
  <dc:creator>Santermans, Eva</dc:creator>
  <dc:creator>Hens, Niel</dc:creator>
  <dc:creator>Goossens, Herman</dc:creator>
  <dc:creator>Verhoye, Marleen</dc:creator>
  <dc:creator>Van der Linden, Annemie</dc:creator>
  <dc:creator>Berneman, Zwi</dc:creator>
  <dc:creator>Hendrix, Sven</dc:creator>
  <dc:creator>Ponsaerts, Peter</dc:creator>
  <dc:description>Background: Promoting the neuroprotective and repair-inducing effector functions of microglia and macrophages, by means of M2 polarisation or alternative activation, is expected to become a new therapeutic approach for central nervous system (CNS) disorders in which detrimental pro-inflammatory microglia and/or macrophages display a major contribution to the neuropathology. In this study, we present a novel in vivo approach using intracerebral grafting of mesenchymal stem cells (MSC) genetically engineered to secrete interleukin 13 (IL13-MSC).Methods: In the first experimental setup, control MSC and IL13-MSC were grafted in the CNS of eGFP+ bone marrow chimaeric C57BL/6 mice to histologically evaluate IL13-mediated expression of several markers associated with alternative activation, including arginase1 and Ym1, on MSC graft-recognising microglia and MSC graft-infiltrating macrophages. In the second experimental setup, IL13-MSC were grafted on the right side (or on both the right and left sides) of the splenium of the corpus callosum in wild-type C57BL/6 mice and in C57BL/6 CX3CR1eGFP/+CCR2RFP/+ transgenic mice. Next, CNS inflammation and demyelination was induced by means of a cuprizone-supplemented diet. The influence of IL13-MSC grafting on neuropathological alterations was monitored by non-invasive T 2-weighted magnetic resonance imaging (MRI) and quantitative histological analyses, as compared to cuprizone-treated mice with control MSC grafts and/or cuprizone-treated mice without MSC injection.Results: In the first part of this study, we demonstrate that MSC graft-associated microglia and MSC graft-infiltrating macrophages are forced into alternative activation upon grafting of IL13-MSC, but not upon grafting of control MSC. In the second part of this study, we demonstrate that grafting of IL13-MSC, in addition to the recruitment of M2 polarised macrophages, limits cuprizone-induced microgliosis, oligodendrocyte death and demyelination. Furthermore, we here demonstrate that injection of IL13-MSC at both sides of the splenium leads to a superior protective effect as compared to a single injection at one side of the splenium.Conclusions: Controlled and localised production of IL13 by means of intracerebral MSC grafting has the potential to modulate cell graft- and pathology-associated microglial/macrophage responses, and to interfere with oligodendrocyte death and demyelinating events in the cuprizone mouse model.</dc:description>
  <dc:source>Journal of Neuroinflammation 13(1) 288</dc:source>
  <dc:subject>Interleukin 13</dc:subject>
  <dc:subject>Mesenchymal stem cells</dc:subject>
  <dc:subject>Magnetic resonance imaging</dc:subject>
  <dc:title>Intracerebral transplantation of interleukin 13-producing mesenchymal stem cells limits microgliosis, oligodendrocyte loss and demyelination in the cuprizone mouse model</dc:title>
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