Mesenchymal Stem Cells in a Transgenic Mouse Model of Multiple System Atrophy: Immunomodulation and Neuroprotection

Sylvia Stemberger,Gregor K Wenning,Günter Lepperdinger,Markus Reindl,Angelika Jamnig,Nadia Stefanova,Markus Schuelke

doi:10.1371/journal.pone.0019808

Sylvia Stemberger, Gregor K Wenning + Show 5 more

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https://doi.org/10.1371/journal.pone.0019808

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Abstract

BackgroundMesenchymal stem cells (MSC) are currently strong candidates for cell-based therapies. They are well known for their differentiation potential and immunoregulatory properties and have been proven to be potentially effective in the treatment of a large variety of diseases, including neurodegenerative disorders. Currently there is no treatment that provides consistent long-term benefits for patients with multiple system atrophy (MSA), a fatal late onset α-synucleinopathy. Principally neuroprotective or regenerative strategies, including cell-based therapies, represent a powerful approach for treating MSA. In this study we investigated the efficacy of intravenously applied MSCs in terms of behavioural improvement, neuroprotection and modulation of neuroinflammation in the (PLP)-αsynuclein (αSYN) MSA model.Methodology/Principal FindingsMSCs were intravenously applied in aged (PLP)-αSYN transgenic mice. Behavioural analyses, defining fine motor coordination and balance capabilities as well as stride length analysis, were performed to measure behavioural outcome. Neuroprotection was assessed by quantifying TH neurons in the substantia nigra pars compacta (SNc). MSC treatment on neuroinflammation was analysed by cytokine measurements (IL-1α, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, GM-CSF, INFγ, MCP-1, TGF-β1, TNF-α) in brain lysates together with immunohistochemistry for T-cells and microglia.Four weeks post MSC treatment we observed neuroprotection in the SNc, as well as downregulation of cytokines involved in neuroinflammation. However, there was no behavioural improvement after MSC application.Conclusions/SignificanceTo our knowledge this is the first experimental approach of MSC treatment in a transgenic MSA mouse model. Our data suggest that intravenously infused MSCs have a potent effect on immunomodulation and neuroprotection. Our data warrant further studies to elucidate the efficacy of systemically administered MSCs in transgenic MSA models.

Highlights

Multiple system atrophy (MSA) denotes an adult-onset neurodegenerative disorder of relentless progression and unknown aetiology that is clinically characterized by the variable combination of autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia, and pyramidal signs
Cell transplantation and tracing of green fluorescent protein (GFP) Mesenchymal stem cells (MSC) Two groups of aged (PLP)-a-SYN mice were included in the study, one group receiving 500,000 cells/150 ml of saline through the tail vein designated (PLP)-aSYN+MSC, and one group serving as controls with an equal amount of saline only into the tail vein termed (PLP)-aSYN
To control the efficiency of the antibody in fixed tissue, brain sections from (PLP)-aSYN control group served as negative control (Figure 1C) while brain sections from C57BL/ 6-Tg(UBC-GFP)30Scha/J served as positive (Figure 1D) control

Summary

Introduction

Multiple system atrophy (MSA) denotes an adult-onset neurodegenerative disorder of relentless progression and unknown aetiology that is clinically characterized by the variable combination of autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia, and pyramidal signs. Mesenchymal stem cells (MSC) are currently strong candidates for cell-based therapies. They are well known for their differentiation potential and immunoregulatory properties and have been proven to be potentially effective in the treatment of a large variety of diseases, including neurodegenerative disorders. There is no treatment that provides consistent long-term benefits for patients with multiple system atrophy (MSA), a fatal late onset asynucleinopathy. Neuroprotective or regenerative strategies, including cell-based therapies, represent a powerful approach for treating MSA. In this study we investigated the efficacy of intravenously applied MSCs in terms of behavioural improvement, neuroprotection and modulation of neuroinflammation in the (PLP)-asynuclein (aSYN) MSA model

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