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Using human neural stem cells to model neurological disease

Key Points

  • Many common neurological diseases have an underlying genetic basis that can be modelled in transgenic animals. However, animal models do not always faithfully reproduce the human syndrome. The urgent need for therapeutics that are aimed at neuroprotection underscores the necessity for alternative model systems.

  • The study of the diseased human brain is crucial for understanding how mutant proteins lead to neuronal cell death. Unfortunately, this tissue is scarce and difficult to manipulate in vitro.

  • Human stem cells represent a renewable source of human neural tissue that is naturally mitotic without transformation or immortalization. Stem cells can be generated from embryonic, fetal brain and adult brain tissue. Cells that are derived from the different sources have different characteristics that make them more or less useful for modelling neurological disease.

  • Isolation of stem cells from diseased tissues might help to uncover mechanisms of cell death that have been seen in non-human models. Furthermore, mutations can be introduced into both mitotic and non-mitotic neuroepithelial cells through viral vectors or homologous recombination.

  • Neural stem cells can be induced to differentiate into mature, physiologically active neurons and glia, and can be assessed in an undifferentiated or differentiated state and after engraftment.

  • Stem-cell models allow the analysis of neuronal and glial subtypes simultaneously, and they can be assessed using current microarray technologies as well as other conventional activity and expression assays. Stem cells, of course, also have their disadvantages.

  • Examples of how stem cells can be used to model specific neurodegenerative conditions are given.

  • Further experimentation with stem cells and establishment of disease models will provide an important system to test signal-transduction pathways and disease mechanisms in human cells before clinical trials are attempted.

  • Human stem-cell models should be used in parallel with current transgenic animal models as each approach has important strengths.

Abstract

Although many common neurological diseases can be modelled in rodents, in many cases these animal models do not faithfully reproduce the human syndrome at either the molecular or anatomical levels — perhaps owing to important species differences. The study of diseased human brain tissue is therefore crucial for understanding how mutant proteins or toxins might lead to neuronal dysfunction. Unfortunately, this tissue is both scarce and difficult to manipulate. Human stem cells represent a renewable source of tissue that can generate both neurons and glia. Studies that use human stem cells from diseased tissues or stem cells that have been engineered to express specific mutant proteins promise to provide new insights into the mechanisms that underlie neurological diseases.

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Figure 1: Strategies for establishing a stem-cell model for an inherited neurodegenerative disease and the potential mode of assessment.
Figure 2: Expression of GFP or α-synuclein transgenes in neurospheres and differentiated human neural stem cells.

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Acknowledgements

Thanks to S. Behrstock for helpful discussions. B.L.S. is supported by the Swiss Foundation for Grants in Biology and Medicine. Viral vectors used to transduce neurospheres were courtesy of P. Aebischer, Lausanne, Switzerland.

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Correspondence to Clive N. Svendsen.

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The authors declare no competing financial interests.

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DATABASES

LocusLink

DJ1

HD

Hprt

PARK2

SNCA

SOD1

OMIM

Alzheimer disease

Amyotrophic lateral sclerosis

Huntington disease

Parkinson disease

FURTHER INFORMATION

Stem-cell research program — Waisman Center

Wisconsin stem-cell research program

Glossary

TRANSFORMATION

In terms of a neoplastic phenotype, a condition in which a specific genetic alteration(s) promotes dysregulated growth and proliferation, leading to a malignant phenotype.

GLIA

A support cell in the central nervous system. The three types of glia are astrocytes, oligodendrocytes and microglia.

KNOCK-OUT

A technique in which homologous recombination is used to inactivate a gene from its endogenous locus to create a null phenotype.

KNOCK-IN

A technique in which homologous recombination is used to insert a gene into a selected chromosomal location.

HETEROLOGOUS RANDOM INTEGRATION

A technique in which specific genes are introduced into the genome through pronuclear micro-injection, and integrate at random into unpredictable sites of the genome.

DOPAMINERGIC NEURONS

Neurons that synthesize and release the catecholaminergic transmitter dopamine.

SUBSTANTIA NIGRA PARS COMPACTA

The specific midbrain region that degenerates in Parkinson disease; part of the basal ganglia that innervates the striatum with dopaminergic fibres that are essential for movement initiation.

FIBRILS

An abnormal protein conformation that consists of organized filamentous structures seen in protein aggregates.

LEWY BODIES

Proteinaceous cellular deposits or inclusion bodies that contain ubiquitin, α-synuclein and other proteins; considered a hallmark of Parkinson disease histopathology.

EXCITOTOXINS

Glutamatergic agonists that can activate the voltage-sensitive NMDA (N-methyl D-aspartate) receptor allowing calcium influx, consequent activation of calcium-regulated enzymes and cell death.

BASAL GANGLIA

A group of interconnected nuclei in the forebrain and midbrain that includes the striatum (putamen and caudate nucleus), globus pallidus, subthalamic nucleus, ventral tegmental area and substantia nigra.

INNER CELL MASS

A group of cells found in the embryonic blastocyst that make up the embryo proper.

BLASTOCYST

In mammalian development, a thin hollow sphere that consists of the inner cell mass and the trophoblast, which form the placenta.

EMBRYOID BODY

Aggregates of differentiated and undifferentiated cells that are derived from embryonic stem cells in culture.

GERM LAYERS

Three primordial cell layers from which all tissues and organs arise.

SENESCENCE

The process of ageing.

SUBVENTRICULAR ZONE

The naturally neurogenic region that lines the ventricles of the adult brain.

HIPPOCAMPUS

A naturally neurogenic region of the human forebrain that is important for memory formation.

DIFFERENTIAL DISPLAY ANALYSIS

A technique that is used to assess the expression of multiple genes that concurrently uses PCR amplification of mRNA and resolution on a DNA sequencing gel.

ASTROCYTE

A type of glial cell, or support cell, in the brain that can alter the extracellular milieu and ionic concentration owing to the expression of various transporters and channel proteins.

CORTEX

The outer grey matter layer of the forebrain.

RNA INTERFERENCE

(RNAi). A process by which double-stranded RNA silences specifically the expression of homologous genes through degradation of their cognate mRNA.

STRIATUM

A region of the forebrain that comprises the caudate nucleus and putamen; important for regulation of motor movement; it is primarily affected in Huntington disease and secondarily affected in Parkinson disease.

OLIGODENDROCYTE

A type of glial, or support, cell that is found in the central nervous system, and is responsible for the myelination of axons.

NEURITE

Any process that extends from the cell body of the neuron, such as the dendrite or axon.

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Jakel, R., Schneider, B. & Svendsen, C. Using human neural stem cells to model neurological disease. Nat Rev Genet 5, 136–144 (2004). https://doi.org/10.1038/nrg1268

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