Clinical Science (2005) 108, 13–22 (Printed in Great Britain) 13 R E V I E W Neural stem cells and cell replacement therapy: making the right cells Angela BITHELL and Brenda P. WILLIAMS Institute of Psychiatry, Department of Psychological Medicine, PO Box 52, De Crespigny Park, London SE5 8AF, U.K. A B S T R A C T The past few years have seen major advances in the field of NSC (neural stem cell) research with increasing emphasis towards its application in cell-replacement therapy for neurological disorders. However, the clinical application of NSCs will remain largely unfeasible until a comprehensive understanding of the cellular and molecular mechanisms of NSC fate specification is achieved. With this understanding will come an increased possibility to exploit the potential of stem cells in order to manufacture transplantable NSCs able to provide a safe and effective therapy for previously untreatable neurological disorders. Since the pathology of each of these disorders is determined by the loss or damage of a specific neural cell population, it may be necessary to generate a range of NSCs able to replace specific neurons or glia rather than generating a generic NSC population. Currently, a diverse range of strategies is being investigated with this goal in mind. In this review, we focus on the relationship between NSC specification and differentiation and discuss how this information may be used to direct NSCs towards a particular fate. INTRODUCTION Considerable media attention has brought stem cell research into the spotlight, not least because of the exciting possibilities of its application in cell replace- ment therapies for neurological disorders using NSCs (neural stem cells). Despite the obvious benefits promised by this field and some encouraging preliminary studies, in reality there still remains a gulf between theory and practice. Leaving aside the highly contentious ethical debate surrounding the procurement and use of ES (embryonic stem) cells to generate NSCs, as opposed to adult sources of stem cells such as those obtained from bone marrow, we still lack a profound understanding of the basic bio- logy of NSCs and how they can be manipulated to pro- vide consistent and effective results in cell-replacement strategies. NSCs are defined by three main characteristics: they can self-renew, give rise to all of the major neural cell types, i.e. neurons, oligodendrocytes and astrocytes, and can repopulate a damaged region. The first of these characteristics ensures that a pool of NSCs is maintained at the same time as more restricted progeny are generated, and their ability to self-renew provides a convenient app- roach by which to expand the initial NSC population. Despite the use of primary fetal tissue as proof-of- principle in a number of clinical studies, including treat- ment of PD (Parkinson’s disease) patients [1,2], it is not a viable option for large-scale therapeutic application due to a lack of available tissue and ethical considerations. Therefore a readily expandable NSC population, possess- ing an innate ability to make the three major neural cell types and repair damage following injury or disease, is an obvious attraction. Key words: cell replacement therapy, embryonic stem cell, neural stem cell, neurological disorder. Abbreviations: AP, anterior-posterior; BMP, bone morphogenetic protein; CNS, central nervous system; DA, dopaminergic; DV, dorso-ventral; EB, embryoid body; EGF, epidermal growth factor; EGFP, enhanced green fluorescent protein; ES, embryonic stem; FGF2, fibroblast growth factor 2; MCAO, middle cerebral artery occlusion; MN, motor neuron; NPC, neural progenitor cell; NRP, neuronally-restricted progenitor cell; NSC, neural stem cell; PD, Parkinson’s disease; PI, positional identity; RA, retinoic acid; SGL, subgranular layer; Shh, sonic hedgehog; SVZ, sub-ventricular zone; TF, transcription factor. Correspondence: Dr Brenda P. Williams (email b.williams@iop.kcl.ac.uk). C  2005 The Biochemical Society