ALS: a disease of motor neurons and their nonneuronal neighbors.

Recent progress shows that neurons suitable for transplantation can be generated from stem cells in culture, and that the adult brain produces new neurons from its own stem cells in response to injury. These findings raise hope for the development of stem cell therapies in human neurodegenerative disorders. Before clinical trials are initiated, we need to know much more about how to control stem cell proliferation and differentiation into specific phenotypes, induce their integration into existing neural and synaptic circuits, and optimize functional recovery in animal models closely resembling the human disease.

Stem cell therapy for human neurodegenerative disorders-how to make it work.

Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS.

24 a b s t r a c t Cerebrovascular diseases are the third leading cause of death and the primary cause of long-term dis- ability in the United States. The only approved therapy for stroke is tPA, strongly limited by the short therapeutic window and hemorrhagic complications, therefore excluding most patients from its bene- fits. Parkinson's and Huntington's disease are the other two most studied basal ganglia diseases and, as stroke, have very limited treatment options. Inflammation is a key feature in central nervous system dis- orders and it plays a dual role, either improving injury in early phases or impairing neural survival at later stages. Stem cells can be opportunely used to modulate inflammation, abrogate cell death and, therefore, preserve neural function. We here discuss the role of stem cells as restorative treatments for basal gan- glia disorders, including Parkinson's disease, Huntington's disease and stroke, with special emphasis to the recently investigated menstrual blood stem cells. We highlight the availability, proliferative capacity, pluripotentiality and angiogenic features of these cells and explore their present and future experimental and clinical applications. © 2011 Published by Elsevier Ltd.

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Neuroscience and Biobehavioral Reviews

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.

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

Amyotrophic lateral sclerosis (ALS), a multifactorial disease characterized by diffuse motor neuron degeneration, has proven to be a difficult target for stem cell therapy. The primary aim of this study was to determine the long-term effects of intravenous mononuclear human umbilical cord blood cells on disease progression in a well-defined mouse model of ALS. In addition, we rigorously examined the distribution of transplanted cells inside and outside the central nervous system (CNS), migration of transplanted cells to degenerating areas in the brain and spinal cord, and their immunophenotype. Human umbilical cord blood (hUCB) cells (106) were delivered intravenously into presymptomatic G93A mice. The major findings in our study were that cord blood transfusion into the systemic circulation of G93A mice delayed disease progression at least 2–3 weeks and increased lifespan of diseased mice. In addition, transplanted cells survived 10–12 weeks after infusion while they entered regions of motor neuron degen...

Intravenous Administration of Human Umbilical Cord Blood Cells in a Mouse Model of Amyotrophic Lateral Sclerosis: Distribution, Migration, and Differentiation

Jennifer C. Lane

Papers

Intravenous Administration of Human Umbilical Cord Blood Cells in a Mouse Model of Amyotrophic Lateral Sclerosis: Distribution, Migration, and Differentiation