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Stem Cells and Neurological Disease the Transplant Site J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.5.557 on 1 May 2003. Downloaded from EDITORIAL 553 Stem cells shown to survive and ameliorate behav- ................................................................................... ioural deficits in an animal mode of Par- kinson’s disease,3 although in this study 20% of rats still developed teratomas at Stem cells and neurological disease the transplant site. In contrast, Kim et al, using a different approach that relies on R A Barker, M Jain,RJEArmstrong, M A Caldwell transfection with Nurr1 (a transcription ................................................................................... factor involved in the differentiation of dopaminergic cells), have demonstrated The therapeutic implications and application of stem cells for functional efficacy without tumour formation.4 the nervous system Human embryonic stem cells have now been isolated5 and grown in culture with enrichment for neuronal lineages, here has recently been a great deal of (c) ability to migrate and disseminate possible through exposure to a combina- interest in stem cells and the nerv- following implantation within the adult tion of growth factors and mitogens.6 Tous system, in terms of their poten- CNS; These cells, when placed in the develop- tial for deciphering developmental issues (d) possible tropism for areas of path- ing rat brain, can migrate widely and as well as their therapeutic potential. In ology; differentiate in a site specific fashion this editorial we will critically appraise without the formation of teratomas.7 the different types of stem cells, their (e) ease of manipulation using viral and non-viral gene transfer methods; However, the safety of these cells needs therapeutic implications, and the appli- further investigation before they can be (f) ability to better integrate into normal cations to which they have been put, considered for clinical use. Furthermore, brain cytoarchitecture with the potential with the hope that the hype that the sensitive nature of this technology for physiologically regulated release of surround these cells can be dis- and the ethical issues surrounding it substances. tinguished from the scientific reality. make it a very controversial source of tis- We will briefly discuss the different sue for cell replacement therapy and in WHAT ARE STEM CELLS? types of stem cells and how they have this respect the issue of therapeutic 8 Stem cells were originally defined in the been applied to neurological disease, cloning is a major concern. haematological system, but more re- especially Parkinson’s disease, given the cently have been found in a multitude of accepted view that this is the disease most ADULT NEURAL PRECURSOR CELLS other sites, including the brain. These amenable to cell replacement therapy. Oneofthelonghelddogmasisthatneuro- cells all share the same properties of genesis in the adult mammalian central self-renewal and multipotentiality1 and nervous system (CNS) does not occur, various different types and therapeutic EMBRYONIC STEM CELLS although there is now ample evidence to strategies have been defined with respect suggest that this is not the case. New Embryonic stem cells are derived from neurons are derived in adulthood from a to the nervous system (Table 1, fig 1). the inner cell mass of the embryonic The reasons for these cells receiving population of adult neural precursor blastula and are pluripotent with great cells (NPCs), which are primarily found such attention for the treatment of proliferative potential, although with neurological disorders relates to their: in the subependymal layer of the ven- this comes the risk of teratomas. Much tricular zone and the dentate gyrus of (a) capacity to proliferate in culture with of the work to date has concentrated on the hippocampus, although they are also http://jnnp.bmj.com/ the prospect that large numbers of cells mouse derived embryonic stem cells, probably found in other sites.910 How- can be derived from a limited source; which can be made to differentiate into ever, the behaviour of the NPCs found in (b) potential to be harvested from the neurons, including dopaminergic all these sites is different, and may relate patients themselves; neurons.2 These latter cells have been as much to the environment in which Table 1 Essential properties of stem cells for use in clinical transplantation on September 30, 2021 by guest. Protected copyright. Disease Principle function required of stem cells Cell replacement Parkinson’s disease Nigrostriatal dopamine neurons Huntington’s disease GABAergic striatal projection neurons Alzheimer’s (and other dementias) Diffuse neuronal replacement, including basal forebrain cholinergic Multiple system atrophy (MSA) Nigrostriatal and striatal output neurones Hippocampal damage (eg global ischaemia) Hippocampal neurones especially those of CA1 Focal ischaemic damage Broad phenotypes required; dependent on site Traumatic brain injury Broad phenotypes required; dependent on site Spinal injury Projection neurones (glutamate); remyelination Amyotrophic-lateral sclerosis Replacement of alpha motorneurons Multiple sclerosis and other demyelinating conditions Remyelination through oligodendrocytes Drug delivery Epilepsy Local GABA Chronic pain Analgesic compounds such as met-enkephalin and endorphins Genetic defects, eg Metabolic enzymes Mucopolysaccaroidosis VII β-glucuronidase Tay-Sachs disease β-hexosaminidase A Intracerebral malignancy Anti-mitotic drug; modified viruses “growth factor responsive conditions” Support of diverse neuronal populations www.jnnp.com J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.5.557 on 1 May 2003. Downloaded from 554 EDITORIAL these cells may also originate from glia.28 Radial glia have classically been considered to be “scaffolding” cells along which cortical neuroblasts migrate to reach their final destination, after which they differentiate into astrocytes. How- ever, recent in vitro and in situ studies suggest that the radial glial cells may be responsible for the production of new- born neurons, as well as their guidance to their final destinations within the cortex.29 The exact relationship of this cell type to the NSCs derived from the neuroepithelium is yet to be elucidated, although it is possible that as develop- mental time increases, stem cells have either neuroepithelial, radial glial, or finally astroglial characteristics, which all share the characteristic of nestin expression.28 The isolation of these cells is compli- cated because their culturing inevitably leads to a mixed population of progenitor and stem cells, which can better be described as expanded neural precursors (ENPs). In addition, the proliferation of ENPs in culture is not indefinite because The different types of stem cells there appears to be a set number of population doublings—the so-called “Hayflick limit”, equivalent to approxi- they find themselves as to their intrinsic brain are capable of migration and mately 50 population doublings30 after properties. For example, nigral NPCs survival and in vitro can be made to which non-transformed cells enter repli- appear to only differentiate into astro- express markers of astrocytes, oligoden- cative senescence and stop dividing. This cytes in situ or when grafted to the adult droglia, and neurons.19 effect seems to be species dependent, nigra, but when they are cultured in vitro Indeed they have even been associated and although greater for human than or transplanted into the hippocampus with some functional benefit in a rodent 11 rodent ENPs, obviously has important they can form neurons. The function of model of Parkinson’s disease when implications for their clinical applica- these newborn neurons in the adult CNS transfected with the dopamine synthetic tion. Attempts to circumvent this prob- 20 is not known but they do have the char- enzyme tyrosine hydroxylase. However, lem with human cells has employed acteristics of mature neurons with ap- the robustness and efficiency of this sys- either a modification of the culture propriate neurophysiological properties tem to produce neural cells is still poor, technique31 or the use of transducing and evidence of integration into neuro- as is its widespread applicability to other vectors encoding an immortalising nal networks with functional synaptic types of non-neural stem cells. There is oncogene.32 These genetic manipulations http://jnnp.bmj.com/ transmission and behavioural effects.12 13 some evidence from cDNA microarray may alter the behaviour of these cells Although much of this work has been analysis that different stem cells may in even without tumorigenesis, and thus done in rodents there is now evidence of fact have similar phenotypic potential extrapolation of results from such cells neurogenesis in the adult human irrespective of origin21–23 and, therefore, it to those found in the developing and hippocampus,14 with cells being grown is theoretically possible that stem cells adult CNS must be carried out with cau- from the adult human CNS.15 Thus, the derived from non-neural systems may be tion. potential for autologous grafts is possi- used for neural cell therapy through a For ENPs to be of clinical value, they ble, assuming that the NPCs are not transdifferentiation process. However, not only need to be propagated long term on September 30, 2021 by guest. Protected copyright. themselves involved in the disease there have been recent concerns that in culture, but must be able to differenti- process,16 and has indeed already
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