Abstract
To model human neural-cell-fate specification and to provide cells for regenerative therapies, we have developed a method to generate human neural progenitors and neurons from human embryonic stem cells, which recapitulates human fetal brain development. Through the addition of a small molecule that activates canonical WNT signaling, we induced rapid and efficient dose-dependent specification of regionally defined neural progenitors ranging from telencephalic forebrain to posterior hindbrain fates. Ten days after initiation of differentiation, the progenitors could be transplanted to the adult rat striatum, where they formed neuron-rich and tumor-free grafts with maintained regional specification. Cells patterned toward a ventral midbrain (VM) identity generated a high proportion of authentic dopaminergic neurons after transplantation. The dopamine neurons showed morphology, projection pattern, and protein expression identical to that of human fetal VM cells grafted in parallel. VM-patterned but not forebrain-patterned neurons released dopamine and reversed motor deficits in an animal model of Parkinson's disease.
Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / pathology
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Animals
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Body Patterning / drug effects
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Body Patterning / genetics
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Cell Culture Techniques / methods*
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cell Lineage / drug effects
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Cell Lineage / genetics
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Cell Survival / genetics
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Cells, Cultured
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Dopamine / metabolism
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Dopaminergic Neurons / drug effects
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Dopaminergic Neurons / metabolism
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Electrophysiological Phenomena / drug effects
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Embryonic Stem Cells / cytology*
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Embryonic Stem Cells / drug effects
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Embryonic Stem Cells / metabolism
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Gene Expression Regulation / drug effects
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Glycogen Synthase Kinase 3 / metabolism
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Humans
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Motor Activity / drug effects
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Neural Stem Cells / cytology*
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Neural Stem Cells / drug effects
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Neural Stem Cells / metabolism
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Neural Stem Cells / transplantation
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Neural Tube / drug effects
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Neural Tube / embryology
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Neurons / cytology*
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Neurons / drug effects
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Neurons / metabolism
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Organ Specificity / drug effects
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Organ Specificity / genetics
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Phenotype
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Protein Kinase Inhibitors / pharmacology
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Rats
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Telencephalon / cytology
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Telencephalon / drug effects
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Telencephalon / metabolism
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Wnt Signaling Pathway / drug effects
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Wnt Signaling Pathway / genetics
Substances
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Protein Kinase Inhibitors
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Glycogen Synthase Kinase 3
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Dopamine