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

• Published in: Journal of neuroinflammation Vol. 13; no. 1; p. 288
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England BioMed Central 09.11.2016
• Subjects: Animals; Cell Line, Transformed; Cuprizone - toxicity; Cytokines - genetics; Cytokines - metabolism; Demyelinating Diseases - chemically induced; Demyelinating Diseases - diagnostic imaging; Demyelinating Diseases - pathology; Demyelinating Diseases - surgery; Disease Models, Animal; Glial Fibrillary Acidic Protein - metabolism; Gliosis - etiology; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Interleukin-13 - metabolism; Magnetic Resonance Imaging; Mesenchymal Stem Cell Transplantation; Mesenchymal Stromal Cells - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Monoamine Oxidase Inhibitors - toxicity; Myelin Basic Protein - metabolism; Oligodendroglia - drug effects; Oligodendroglia - pathology; Neuroinflammation; Interleukin 13; Transplantation; Magnetic resonance imaging; Mesenchymal stem cells
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-016-0756-7

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). 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 CX CR1 CCR2 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 -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. 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. 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.