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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1294-1301
Number of pages8
JournalNature Neuroscience
Volume11
Issue number11
DOIs
StatePublished - Nov 2008

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Motor Neuron Disease
Astrocytes
Transplantation
Amyotrophic Lateral Sclerosis
Motor Neurons
Neuroglia
Amino Acid Transport System X-AG
Forelimb
Rodentia
Survival
Cervical Cord

ASJC Scopus subject areas

  • Neuroscience(all)

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Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. / Lepore, Angelo C.; Rauck, Britta; Dejea, Christine; Pardo, Andrea C.; Rao, Mahendra S.; Rothstein, Jeffrey D; Maragakis, Nicholas J.

In: Nature Neuroscience, Vol. 11, No. 11, 11.2008, p. 1294-1301.

Research output: Contribution to journalArticle

Lepore, Angelo C. ; Rauck, Britta ; Dejea, Christine ; Pardo, Andrea C. ; Rao, Mahendra S. ; Rothstein, Jeffrey D ; Maragakis, Nicholas J. / Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. In: Nature Neuroscience. 2008 ; Vol. 11, No. 11. pp. 1294-1301.
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