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Brain 2007 130(5):1263-1275; doi:10.1093/brain/awm070
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© The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Environmental signals regulate lineage choice and temporal maturation of neural stem cells from human embryonic stem cells

Alexis J. Joannides1, Daniel J. Webber1, Olivier Raineteau1, Claire Kelly2, Karen-Amanda Irvine1, Colin Watts1, Anne E. Rosser2, Paul J. Kemp2, William F. Blakemore1, Alastair Compston1, Maeve A. Caldwell1, Nicholas D. Allen2 and Siddharthan Chandran1

1Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge and 2School of Biosciences, University of Cardiff, UK

Correspondence to: Siddharthan Chandran, MRCP, PhD, Centre for Brain Repair, Department of Clinical Neurosciences, CB2 2PY, Cambridge, UK E-mail: sc222{at}cam.ac.uk

Human embryonic stem cells (hESCs) are a potential source of defined tissue for cell-based therapies in regenerative neurology. In order for this potential to be realized, there is a need for the evaluation of the behaviour of human embryonic stem cell-derived neural stem cells (hES-NSCs) both in the normal and the injured CNS. Using normal tissue and two experimental models, we examined the response of clinically compatible hES-NSCs to physiological and pathological signals. We demonstrate that the phenotypic potential of a multipotent population of hES-NSCs is influenced by these cues both in vitro and in vivo. hES-NSCs display a temporal profile of neurogenic and gliogenic differentiation, with the generation of mature neurons and glia over 4 weeks in vitro, and 20 weeks in the uninjured rodent brain. However, transplantation into the pathological CNS accelerates maturation and polarizes hES-NSC differentiation potential. This study highlights the role of environmental signals in determining both lineage commitment and temporal maturation of human neural stem cells. Controlled manipulation of environmental signals appropriate to the pathological specificity of the targeted disease will be necessary in the design of therapeutic stem cell-based strategies.

Key Words: human embryonic stem cells; neural stem cells; temporal maturation; phenotypic potential; cell transplantation

Abbreviations: DG , dentate gyrus; hES-NSCs , human embroyonic stem cell-derived neural stem cells; HNM , human neuralizing medium; NPCs , neural precursor cells; BMP , bone morphogenetic protein

Received December 6, 2006. Revised February 9, 2007. Accepted March 12, 2007.


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