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

Abstract

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.

• Authors: Debbie Le Blon, Caroline Guglielmetti, Chloé Hoornaert, Alessandra Quarta, Jasmijn Daans, Dearbhaile Dooley, Evi Lemmens, Jelle Praet, Nathalie De Vocht, Kristien Reekmans, Eva Santermans, Niel Hens, Herman Goossens, Marleen Verhoye, Annemie Van der Linden, Zwi Berneman, Sven Hendrix, Peter Ponsaerts
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 13 Issue 1 Pg. 288 (11 09 2016) ISSN: 1742-2094 [Electronic] England
• PMID: 27829467 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Glial Fibrillary Acidic Protein
• Interleukin-13
• Monoamine Oxidase Inhibitors
• Myelin Basic Protein
• Green Fluorescent Proteins
• Cuprizone

Topics

• Animals
• Cell Line, Transformed
• Cuprizone (toxicity)
• Cytokines (genetics, metabolism)
• Demyelinating Diseases (chemically induced, diagnostic imaging, pathology, surgery)
• Disease Models, Animal
• Glial Fibrillary Acidic Protein (metabolism)
• Gliosis (etiology)
• Green Fluorescent Proteins (genetics, metabolism)
• Interleukin-13 (metabolism)
• Magnetic Resonance Imaging
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Monoamine Oxidase Inhibitors (toxicity)
• Myelin Basic Protein (metabolism)
• Oligodendroglia (drug effects, pathology)