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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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{
  "DOI": "10.1186/s12974-016-0756-7", 
  "container_title": "Journal of Neuroinflammation", 
  "title": "Intracerebral transplantation of interleukin 13-producing mesenchymal stem cells limits microgliosis, oligodendrocyte loss and demyelination in the cuprizone mouse model", 
  "issued": {
    "date-parts": [
      [
        2016, 
        11, 
        9
      ]
    ]
  }, 
  "abstract": "<p><strong>Background: </strong>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).</p><p><strong>Methods: </strong>In the first experimental setup, control MSC and IL13-MSC were grafted in the CNS of eGFP<sup>+</sup> 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 <i>splenium</i> of the <i>corpus callosum</i> in wild-type C57BL/6 mice and in C57BL/6 CX<sub>3</sub>CR1<sup>eGFP/+</sup>CCR2<sup>RFP/+</sup> 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 <i>T</i> <sub>2</sub>-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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>", 
  "author": [
    {
      "family": "Le Blon, Debbie"
    }, 
    {
      "family": "Guglielmetti, Caroline"
    }, 
    {
      "family": "Hoornaert, Chlo\u00e9"
    }, 
    {
      "family": "Quarta, Alessandra"
    }, 
    {
      "family": "Daans, Jasmijn"
    }, 
    {
      "family": "Dooley, Dearbhaile"
    }, 
    {
      "family": "Lemmens, Evi"
    }, 
    {
      "family": "Praet, Jelle"
    }, 
    {
      "family": "De Vocht, Nathalie"
    }, 
    {
      "family": "Reekmans, Kristien"
    }, 
    {
      "family": "Santermans, Eva"
    }, 
    {
      "family": "Hens, Niel"
    }, 
    {
      "family": "Goossens, Herman"
    }, 
    {
      "family": "Verhoye, Marleen"
    }, 
    {
      "family": "Van der Linden, Annemie"
    }, 
    {
      "family": "Berneman, Zwi"
    }, 
    {
      "family": "Hendrix, Sven"
    }, 
    {
      "family": "Ponsaerts, Peter"
    }
  ], 
  "page": "288", 
  "volume": "13", 
  "type": "article-journal", 
  "issue": "1", 
  "id": "166404"
}
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