Results and Problems in Cell Differentiation

Neural stem cells isolated from the developing and adult brain are an ideal source of cells for use in clinical applications such as cell replacement therapy. The clear advantage of these cells over the more commonly utilised embryonic and pluripotent stem cells is that they are already neurally committed. Of particular importance is the fact that these cells don’t require the same level of in vitro culture that can be cost and labour intensive. Foetal neural stem cells can be readily derived from the foetal brain and expand in culture over time. Similarly, adult stem cells have been explored for their potential in vitro and in vivo animal models. In this chapter we identify the progress made in developing these cells as well as the advantages of taking them forward for clinical use. Neural stem cells may be derived from several sources, and the focus of attention in recent years has been on those from embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. These cells can be readily differentiated down a neural lineage from where they can be further directed into the different cell types of the nervous system. One therapeutic approach for which these cells have been extensively explored is cell replacement therapy (CRT). CRT aims to replace the cells that have been lost due to disease process. Neurodegenerative diseases such as Parkinson’s disease (PD) and Huntington’s disease (HD), where there is focal cell loss, are ideal candidates for this type of approach. It has been shown that primary human foetal cells transplanted into the diseased brain can survive and integrate into the host brain, thereby recreating the lost circuitry and alleviating the motor symptoms of the disease. Proof of principle has been shown in clinical trials to date for both neurodegenerative diseases; however, there is an urgent need to identify an C. M. Kelly Biomedical Science, Cardiff School of Health Sciences, Cardiff Metropolitan University, Cardiff, UK e-mail: ckelly@cardiffmet.ac.uk M. A. Caldwell (*) Trinity College Institute for Neuroscience, Trinity College Dublin, Dublin, Ireland e-mail: Maeve.Caldwell@tcd.ie © Springer International Publishing AG, part of Springer Nature 2018 L. Buzanska (ed.), Human Neural Stem Cells, Results and Problems in Cell Differentiation 66, https://doi.org/10.1007/978-3-319-93485-3_1 3 alternative cell source that can be used to make this approach more viable. Currently, the source of cells is primary human foetal tissue taken within a restricted time window, around the time of birth of these neurons. Specifically, for PD this would be 4–6 weeks postconception and slightly later for HD, 8–12 weeks postconception. This restricted time window places significant constraints on the feasibility of largescale clinical application. In addition several donors are required per patient, an issue compounded by the fact that bilateral transplants in PD require cells from approximately six foetuses and the time line for collecting this tissue is restricted to 7 days (thus causing logistical problems for coordinating cell collection, surgery and pathological screening of cells) and they are difficult to standardise. Hence, there is a need to identify a new source of cells that would make this possible. Indeed, for any type of cells to be considered as a cell replacement therapy, there are a number of critical issues that should be addressed: (1) the biology of the cells should be completely defined; (2) it should be possible to both expand and store these cells in clinically useful quantities; (3) they should have a reliable differentiation potential, i.e. their neurogenic potential must remain stable after passaging; (4) they must be able to restore function following transplantation; and (5) they must not undergo malignant transformation over time. ES and iPS cells are being extensively explored for this purpose. ES and iPS cells are a pluripotent source of cells and thus require manipulation in vitro to direct them firstly to a neuronal fate and furthermore to a cell type-specific phenotype. An alternative approach is to seek to identify stem cells that are already committed to a neural lineage (i.e. tissue-specific) and, furthermore, from an even more restricted lineage, for example, striatal precursors from which it may be easier to drive an explicitly striatal phenotype, as required for HD. In addition, if these cells could survive cryopreservation, this would ease current practical constraints associated with scheduling the neurosurgery and would also permit at least some standardisation of the cells, which cannot currently be achieved for primary foetal tissue. Specifically, foetal tissue can only be reliably held in culture (using media to reduce metabolic processes, i.e. ‘hibernation’) for a short period of time (up to 8 days) which is an insufficient period of time to permit full quality control of the tissue (Hurelbrink et al. 2000). Furthermore, the multipotential nature of these cells means they are less likely to give rise to fast-growing tumours following grafting, a constant risk associated with pluripotent-derived neural cells. The focus of this chapter will be on those cells found in the developing and adult brain that have ‘neural stem cell’ characteristics. Within the developing and adult brain, there are populations of neural cells that have stem cell-like characteristics. By definition ‘neural stem cell’ describes a multipotent stem cell that can self-renew and give rise to one or multiple neural or glial lineages. Furthermore, the terms ‘neural progenitor cell’ and ‘neural precursor cell’ refer to a lineage restricted to an unspecified neural cell or, if further down the developmental pathway, specified to a brain subregion. As well as being present throughout development, stem cell populations are present in adult tissues, where they may be continually active, such as stem cells that underlie the constant renewal of the skin, or may be largely quiescent but capable of being triggered to proliferate if the conditions are right, as for some populations in the adult CNS. It cannot be 4 C. M. Kelly and M. A. Caldwell