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

Angelo C. Lepore; Britta Rauck; Christine Dejea; Andrea C. Pardo; Mahendra S. Rao; Jeffrey D. Rothstein; Nicholas J. Maragakis

doi:10.1038/nn.2210

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

Angelo C. Lepore, Britta Rauck, Christine Dejea, Andrea C. Pardo, Mahendra S. Rao, Jeffrey D. Rothstein, Nicholas J. Maragakis

School of Medicine

Research output: Contribution to journal › Article › peer-review

297 Scopus citations

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 (SOD1^G93A). 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 SOD1^G93A 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.

Original language	English (US)
Pages (from-to)	1294-1301
Number of pages	8
Journal	Nature neuroscience
Volume	11
Issue number	11
DOIs	https://doi.org/10.1038/nn.2210
State	Published - Nov 2008

ASJC Scopus subject areas

Neuroscience(all)

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@article{138f88f0e5174f1ba8b8a51f387922cb,

title = "Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease",

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.",

author = "Lepore, {Angelo C.} and Britta Rauck and Christine Dejea and Pardo, {Andrea C.} and Rao, {Mahendra S.} and Rothstein, {Jeffrey D.} and Maragakis, {Nicholas J.}",

note = "Funding Information: 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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AU - Dejea, Christine

AU - Pardo, Andrea C.

AU - Rao, Mahendra S.

AU - Rothstein, Jeffrey D.

AU - Maragakis, Nicholas J.

N1 - Funding Information: 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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N2 - 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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Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease

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