A feast of neural stem cells

It is now clear that neural stem cells, which are self-renewing multipotent cells able to give rise to neurons, astrocytes or oligodendrocytes, are found in a great variety of regions in the vertebrate developing and adult nervous system. Cells with these properties can also be derived from embryonic stem(ES) cells in vitro using protocols inspired by our understanding of neural stem cells in the intact nervous system. The ability to culture neural stem cells in vitro and to direct their differentiation into specific cell types has also opened up the possibility of generating neurons for therapeutic purposes; for example, transplantation of additional dopamine-producing neurons to alleviate loss of such cells in Parkinson's disease. With the advent of human ES cell lines, interest in neural stem cells is growing apace. This book comprises a collection of chapters addressing the many different contexts in which neural stem cells are found, describing the developmental potential of these cells and their distinctive cellular and molecular characteristics, as well as the therapeutic applications of such cells. The book is intended as a handy guide for a course on stem cell biology for novice and expert alike. However, it is not a textbook, but rather a series of stand-alone essays organised into a loose progression from neural stem cells in the early embryo, in specific regions and in the adult nervous system.FIG1 

This book is an updated version of the first edition, which was published in 2000, and now comprises fifteen chapters. An excellent opening essay from Sally Temple defines neural stem cells and describes their changing potency as development proceeds. This is followed by a series of partially overlapping chapters that address the properties of stem cells in the developing vertebrate central nervous system (by Larysa Pevny; John Kessler and colleagues; Douglas Falls and Marla Luskin), including in the retina (a new chapter for this edition from Iqbal Ahmad and colleagues). Peripheral nervous system/neural crest development and stem cells in cancer are then addressed by Marianne Bronner-Fraser and colleagues. Adult neurogenesis in the cortex and hippocampus, as well as in the olfactory epithelium (another new topic for this edition), is also well reviewed (Daniel Lim and Arturo Alvarez-Buylla;Steven Goldman; Theo Palmer and Fred Gage; James Schwob and Woochan Jang). Other focussed chapters consider the regulation of neural stem cell death (an additional new chapter, from Rizwan Akhtar and Kevin Roth), glial-restricted precursors (Mark Noble and Margot Mayer-Pröschel) and transdifferentiation in the nervous system (Ying Liu and Mahendra Rao). The final chapters address the derivation of neural stem cells from ES cells(Robin Wesselschmidt and John McDonald) and the use of neural stem cells for transplant therapy (Evan Snyder and colleagues).

Overall, these are scholarly, informative, well-written essays. There are,however, some omissions, including an account of vertebrate neural induction and of the multipotent, self-renewing, stem cell-like population in the tail bud, although this cell population gives rise to mesodermal as well as neural derivatives (Cambray and Wilson,2002; Davis and Kirschner,2000; Mathis and Nicolas,2000). Our understanding of vertebrate neurogenesis is also greatly informed by analysis of this process in invertebrates and in Drosophila in particular. For example, recent experiments in the retina that assess loss of the mammalian homologue of Inscuteable have revealed yet again the conservation of gene function from fly to mammal and the crucial importance of mitotic spindle orientation for cell fate symmetry during neurogenesis (Zigman et al.,2005). Although this topic is included in Sally Temple's first chapter, it would also have been great to have a whole chapter on Drosophila neural stem cells from researchers working in the field.

There is also just one chapter that covers the vast topic of neural differentiation of ES cells in vitro. This chapter outlines the basics,including culture methods and conditions for embryoid body formation and for the monolayer culture of ES cells. Protocols for the use of retinoic acid and sonic hedgehog to promote neural differentiation and the generation of specific neuronal cell types in embryoid bodies are also discussed. However,the chapter does not review experiments that directly implicate other signalling pathways (such as FGF, Wnt and Notch signals) in the regulation of ES cell neural differentiation. It would also have been interesting to discuss certain key issues, such as whether it is possible to generate a homogenous neural cell population in vitro and what differences are apparent between neural/neuronal/glial differentiation during embryonic development and in ES cells in vitro. The frequent references to the now discredited work of Hwang Woo Suk also jump out at you and are testimony to the great pressure that this area of research is under and the speed at which this field is moving.

A more discursive approach is taken by the editor Mahendra Rao, who should be applauded for tackling the controversial and fascinating topic of transdifferentiation. This chapter raises important issues that need to be addressed if this phenomenon is to be firmly established as taking place in neural tissue. These include the possibility that cells thought to have transdifferentiated may actually have changed their properties as a result of fusion with a different cell type, and that cells with apparently altered characteristics might have arisen as a result of the activity of contaminating stem cells, rather than owing to the redirection of the gene expression profile of a differentiated cell. There is also a tendency for over interpretation in this field; for example, when a neural crest cell adopts a new fate, this could be interpreted as revealing the broad competence of these cells rather than evidence for a switch between differentiated cell states. As Rao points out, transdifferentiation has great potential as it could be used to generate new tissues from host cells, thereby removing the possibility of rejection by the immune system.

The chapters on adult neurogenesis are particularly well written, with clear nomenclature and a good balance between data and opinion. Daniel Lim and Arturo Alvarez-Buylla consider the similarities between glial cells and adult neural stem cells and conclude that in some cases these are one and the same cell. They also make the intriguing suggestion that the presence of a cilium on B cells (likely sub-ventricular zone stem cells) is an indication of their cell cycle phase. Theo Palmer and Fred Gage provide a particularly thoughtful account of the realities of therapeutic approaches to neuron replacement in the adult brain, concluding that even when technical difficulties are overcome, we still know nothing of the cognitive repercussions of such manipulations. Transplantation therapy using ES cell-derived neural tissue is also discussed by Robin Wesselschmidt and John McDonald, who make the interesting observation that such cells differentiate faster than do adult neural stem cells, and that transplanted ES cells can also remodel the extracellular environment. They go on to suggest that ES cells might be used clinically to modulate the host environment to make it more conducive to regeneration. The use of ES cell-derived neural tissue for creating in vitro models of neurodegenerative diseases that are amenable to drug screening would also be a further topic for a future edition.

Overall, this is a useful collection of essays that is illustrated with plenty of diagrams and colour images, and it is really valuable to have all this information in one place. However, these kinds of collections do have some drawbacks. It is hard for an editor to tell invited authors what to write. This means that there is inevitably some overlap between chapters. Each chapter is also written as a stand-alone piece and requires, particularly in the field of stem cell research, a clear set of definitions. Chapter introductions also serve to acknowledge the breath of the field before defining the specific area to be discussed. This can lead to further frustration for the reader. For example, in numerous introductions to the chapters in this book, we are told that there is some evidence for the existence of stem cells in the spinal cord, together with the suggestion that this evidence may not be compelling, but no one reviews the data. This tendency for repetition and the lack of overall coverage of the subject make the book less appropriate for the novice and as a course guide. I think it will most likely be read for specific chapters by graduate students and experienced researchers that are new to the field. On the other hand, this book really does document the great progress being made in this area of research, so much so that it seems time for a textbook on neural stem cells. Such a book would provide a simpler but more systematic overview of the subject; it might lose some of the very extensive references (including the duplications), but still retain space for inspiring speculation.