Mesenchymal stem cells do not exert direct beneficial effects on CNS remyelination in the absence of the peripheral immune system

Tejedor, Laura Salinas; Berner, Gabriel; Jacobsen, Kristin; Gudi, Viktoria; Jungwirth, Nicole; Hansmann, Florian; Gingele, Stefan; Prajeeth, Chittappen Kandiyil; Baumgärtner, Wolfgang; Hoffmann, Andrea; Skripuletz, Thomas; Stangel, Martin

doi:10.1016/j.bbi.2015.06.024

Cited by 25 publications

(19 citation statements)

References 40 publications

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“…In addition, our own preceding work on cell grafting in the CPZ model at the peak of inflammation and demyelination was also unable to demonstrate any contribution of mesenchymal, neural or haematopoietic cells to remyelination [14]. The latter observation was recently confirmed by a study performed by Salinas Tejedor et al showing that MSC injected at the onset or the peak of oligodendrocyte proliferation during cuprizone-induced demyelination do not exert beneficial effects on remyelination [34]. Although all these studies question the use of MSC to exert direct neuroprotective effects in the CPZ model, we here provide an alternative approach in which we demonstrate that autologous MSC are well-suited as transplantable carrier cells for the direct delivery of a therapeutic protein to the injured CNS, as proven in the current study for the M2-polarising cytokine IL13.…”

Section: Discussionmentioning

confidence: 99%

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

Blon

Guglielmetti

Hoornaert

et al. 2016

J Neuroinflammation

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BackgroundPromoting 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).MethodsIn 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.ResultsIn 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.ConclusionsControlled 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.

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Section: Discussionmentioning

confidence: 99%

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

Blon

Guglielmetti

Hoornaert

et al. 2016

J Neuroinflammation

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“…Likewise, the influence of MSCs on oligodendroglial dynamics under noninflammatory conditions has been controversially discussed. MSCs transplanted upon cuprizonemediated demyelination activated oligodendrogenesis and remyelination [77,78], whereas intravenously or intranasally applied cells did not affect the CNS [79,80]. These observations clearly emphasize the need for further investigations.…”

Section: Exogenous Cell-based Approachesmentioning

confidence: 82%

Recent achievements in stem cell-mediated myelin repair

Jadasz

Lubetzki

Zalc

et al. 2016

Current Opinion in Neurology

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“…This notion has been further supported by data from a murine demyelination model, in which the peripheral immune system is absent. MSCs were found to not exert regenerative functions and did not enter CNS lesions [50,66]. Whereas SPIO particles were found in the CNS, histological staining indicated their uptake by phagocytic leukocytes, which vitally contribute to inflammatory lesion formation and neuronal degeneration.…”

Section: Discussionmentioning

confidence: 95%

Mesenchymal Stromal/Stem Cells Do Not Ameliorate Experimental Autoimmune Encephalomyelitis and Are Not Detectable in the Central Nervous System of Transplanted Mice

Aucouturier

Krasemann

Ernst

et al. 2016

Stem Cells and Development

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Mesenchymal stromal/stem cells (MSCs) constitute progenitor cells that can be isolated from different tissues. Based on their immunomodulatory and neuroprotective functions, MSC-based cell-therapy approaches have been suggested to antagonize inflammatory activity and neuronal damage associated with autoimmune disease of the central nervous system (CNS), for example, multiple sclerosis (MS). Intravenous MSC transplantation was reported to ameliorate experimental autoimmune encephalomyelitis (EAE), the murine model of MS, within days after transplantation. However, systemic distribution patterns and fate of MSCs after administration, especially their potential to migrate into inflammatory lesions within the CNS, remain to be elucidated. This question has of recent become particularly important, since therapeutic infusion of MSCs is now being tested in clinical trials with MS-affected patients. Here, we made use of the established EAE mouse model to investigate migration and therapeutic efficacy of murine bone marrow-derived MSCs. Applying a variety of techniques, including magnetic resonance imaging, immunohistochemistry, fluorescence in-situ hybridization, and quantitative polymerase chain reaction we found no evidence for immediate migration of infused MSC into the CNS of treated mice. Moreover, in contrast to other studies, transplanted MSCs did not ameliorate EAE. In conclusion, our data does not provide substantiation for a relevant migration of infused MSCs into the CNS of EAE mice supporting the hypothesis that potential therapeutic efficacy could be based on systemic effects. Evaluation of possible mechanisms underlying the observed discrepancies in MSC treatment outcomes between different EAE models demands further studies.

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Mesenchymal stem cells do not exert direct beneficial effects on CNS remyelination in the absence of the peripheral immune system

Cited by 25 publications

References 40 publications

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

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

Recent achievements in stem cell-mediated myelin repair

Mesenchymal Stromal/Stem Cells Do Not Ameliorate Experimental Autoimmune Encephalomyelitis and Are Not Detectable in the Central Nervous System of Transplanted Mice

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