Intracerebral transplantation of interleukin 13-producing mesenchymal stem cells limits microgliosis, oligodendrocyte loss and demyelination in the cuprizone mouse model.
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 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 T2-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.
Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
Debbie
D
Le Blon
Bio-Imaging Laboratory, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
Caroline
C
Guglielmetti
Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
Chloé
C
Hoornaert
Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
Alessandra
A
Quarta
Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
Jasmijn
J
Daans
Department of Morphology, Biomedical Research Institute, Hasselt University, Agoralaan building C, 3590, Diepenbeek, Belgium.
Dearbhaile
D
Dooley
Department of Morphology, Biomedical Research Institute, Hasselt University, Agoralaan building C, 3590, Diepenbeek, Belgium.
Evi
E
Lemmens
Bio-Imaging Laboratory, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
Jelle
J
Praet
Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
Nathalie
N
De Vocht
Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
Kristien
K
Reekmans
Center for Statistics, I-Biostat, Hasselt University, Agoralaan building D, 3590, Diepenbeek, Belgium.
Eva
E
Santermans
Center for Statistics, I-Biostat, Hasselt University, Agoralaan building D, 3590, Diepenbeek, Belgium.|Centre for Health Economic Research and Modeling Infectious Diseases (Chermid), University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
Niel
N
Hens
Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
Herman
H
Goossens
Bio-Imaging Laboratory, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
Marleen
M
Verhoye
Bio-Imaging Laboratory, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
Annemie
A
Van der Linden
Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.|Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
Zwi
Z
Berneman
Department of Morphology, Biomedical Research Institute, Hasselt University, Agoralaan building C, 3590, Diepenbeek, Belgium.
Sven
S
Hendrix
Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium. Peter.Ponsaerts@uantwerpen.be.|Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium. Peter.Ponsaerts@uantwerpen.be.|Experimental Cell Transplantation Group, Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Campus Drie Eiken (CDE-S6.51), Universiteitsplein 1, 2610, Antwerp, Wilrijk, Belgium. Peter.Ponsaerts@uantwerpen.be.
Peter
P
Ponsaerts
D000818:Animals; D002461:Cell Line, Transformed; D003471:Cuprizone / Q000633:toxicity*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000473:pathology / Q000601:surgery; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000209:etiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity*; D004676:Myelin Basic Protein / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology*
D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D018793:Interleukin-13; D008996:Monoamine Oxidase Inhibitors; D004676:Myelin Basic Protein; D049452:Green Fluorescent Proteins; D003471:Cuprizone
Interleukin 13; Magnetic resonance imaging; Mesenchymal stem cells; Neuroinflammation; Transplantation