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Focal transplantation–based astrocyte replacement is neuroprotective in a model of motor neuron disease

Nature Neuroscience volume 11, pages 1294–1301 (2008)Cite this article

Abstract

Cellular abnormalities in amyotrophic lateral sclerosis (ALS) are not limited to motor neurons. Astrocyte dysfunction also occurs in human ALS and transgenic rodents expressing mutant human SOD1 protein (SOD1G93A). Here we investigated focal enrichment of normal astrocytes using transplantation of lineage-restricted astrocyte precursors, called glial-restricted precursors (GRPs). We transplanted GRPs around cervical spinal cord respiratory motor neuron pools, the principal cells whose dysfunction precipitates death in ALS. GRPs survived in diseased tissue, differentiated efficiently into astrocytes and reduced microgliosis in the cervical spinal cords of SOD1G93A rats. GRPs also extended survival and disease duration, attenuated motor neuron loss and slowed declines in forelimb motor and respiratory physiological functions. Neuroprotection was mediated in part by the primary astrocyte glutamate transporter GLT1. These findings indicate the feasibility and efficacy of transplantation-based astrocyte replacement and show that targeted multisegmental cell delivery to the cervical spinal cord is a promising therapeutic strategy for slowing focal motor neuron loss associated with ALS.

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Figure 1: GRP transplants robustly survived and migrated in the cervical spinal cords of SOD1G93A rats.
Figure 2: GRP transplants efficiently differentiated into astrocytes and spatially interacted with host ventral horn motor neurons in SOD1G93A cervical spinal cords.
Figure 3: After transplantation into the cervical spinal cords of SOD1G93A rats, transplanted GRPs extended survival and disease duration and slowed declines in forelimb grip strength and motor performance.
Figure 4: After transplantation into cervical spinal cords of SOD1G93A rats, GRPs partially slowed cervical spinal cord motor neuron and GLT1 protein loss, as well as the decline in phrenic nerve CMAPs.
Figure 5: GRP transplants decreased ventral horn microgliosis.

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Acknowledgements

We thank all members of the Maragakis and Rothstein labs for helpful discussion and K. Tanaka for providing GLT1-null mice. This work was supported by the Robert Packard Center for ALS Research (to N.J.M.), the ALS Association (to N.J.M.) and the National Institutes of Health (F32-NS059155 to A.C.L., R01-NS33958 to J.D.R. and R01-NS41680 to J.D.R. and N.J.M.).

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Authors and Affiliations

  1. Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Meyer 6-119, Baltimore, 21287, Maryland, USA

    Angelo C Lepore, Britta Rauck, Christine Dejea, Andrea C Pardo, Jeffrey D Rothstein & Nicholas J Maragakis

  2. Invitrogen Corporation, 1610 Faraday Avenue, Carlsbad, California, USA

    Mahendra S Rao

  3. Department of Neuroscience, The Johns Hopkins University School of Medicine, 600 N. Wolfe St., Meyer 6-109, Baltimore, 21287, Maryland, USA

    Jeffrey D Rothstein

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Contributions

A.C.L. designed and conducted the experiments, analyzed the data, prepared the figures and wrote the manuscript. N.J.M. supervised the project and participated in designing experiments and writing the manuscript. M.S.R. and J.D.R. participated in designing experiments and writing the manuscript. B.R., A.C.P. and C.D. conducted experiments.

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Correspondence to Nicholas J Maragakis.

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Competing interests

M.S.R. works for Invitrogen, which is a supplier of reagents to the stem cell research communuty. M.S.R. was a scientific founder of Q Therapeutics, Inc. and is a non-paid scientific consultant. J.D.R. is a consultant to Ruxton Pharmaceuticals. N.J.M. is a non-paid scientific consultant to Q Therapeutics, Inc.

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Lepore, A., Rauck, B., Dejea, C. et al. Focal transplantation–based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nat Neurosci 11, 1294–1301 (2008). https://doi.org/10.1038/nn.2210

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