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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 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 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 of

(a) capacity to proliferate in culture with of the work to date has concentrated on the , 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

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

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these cells may also originate from .28 Radial glia have classically been considered to be “scaffolding” cells along which cortical migrate to reach their final destination, after which they differentiate into . 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 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 been such a process may be a result of cell ate appropriately, which is influenced attempted in one patient with Parkin- fusion—namely adult somatic cells can both by intrinsic and external factors, son’s disease.17 appear to gain differentiation potential such as the culture conditions.33 This by fusion with less differentiated having been said, neurons differentiat- cells.24 25 ing from growth factor responsive ENPs BONE MARROW AND are typically GABAergic in phenotype, NON-NEURAL STEM CELLS irrespective of species or region from An alternative source of autologous cells EMBRYONIC NEURAL STEM CELLS which the cells were harvested in the for grafting in patients with neurological (NSCs) embryo.34 So for most disorders, espe- disease are those derived from non- Most of the work on stem cells and the cially Parkinson’s disease, it will be neural sources including the bone mar- CNS refers to NSCs that are derived from necessary to switch or regulate their fate row, which contains a range of stem the neuroepithelium of the developing and a number of factors and methods cells. This includes the haematopoietic embryo. These cells respond in vitro to have been suggested for the generation stem cell, which when transplanted into mitogens such as epidermal growth fac- of dopaminergic neurons based on fac- irradiated recipients can migrate into the tor (EGF) and fibroblast growth factor tors known to be important in their nor- brain and differentiate into microglia, (FGF2), and it is possible to expand cells mal development (see also embryonic astrocytes, and possibly neurons.18 In from any region of the brain.26 27 As stem cell section; see figure 2). addition, there are mesenchymal stem development progresses to adulthood Exposure of ENPs to sonic hedgehog cells or bone marrow stromal cells, there is considerable debate over the ori- (Shh)36 or transcription factors, includ- which when engrafted into the adult gin of NSCs, with recent suggestions that ing nurr1,37 has been shown to increase

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ganglia stroke and resultant motor defi- cits. Reassuringly, there has been no evi- dence for tumorigenesis or other adverse effects in the 12 patients who have been reported in the phase I study, although preliminary functional and imaging data are difficult to interpret because of the lack of an adequate control group.51 There is, however, at least some evidence of cell survival based on postmortem data 27 months post-transplantation.52

Demyelinating diseases Development of midbrain dopamine (DA) neurons. Initial specification requires the patterning information that is provided by sonic hedgehog (shh) and fibroblast growth factor 8 (FGF8). ENPs are also being considered to The Lmx1b and nurr1 transcription factors are essential for different aspects of DA replace glial cells that have been lost to differentiation. The ptx3 transcription factor and the retinoid synthesising enzyme Aldh1 are demyelinating or dysmyelinating dis- specific markers of developing DA neurons in the ventral midbrain, but their roles are still ease. Animal models of global hypo- largely unknown. Adapted from Goridis & Rohrer, 2002.35 myelination (eg the shiverer (Shi) mouse) have been used to examine the the yield of dopaminergic neurons ob- the fact that in vitro, NPCs derived from ability of transplanted ENPs to myelinate tained from these cells, although not all the developing ventral mesencephalon axons. Oligodendrocytes constitute a cell types respond to such stimulation, lose the ability to spontaneously differ- very small component of the differenti- for example hNT neurons.38 39 However, entiate into dopaminergic cells after only ated cells that emerge spontaneously in in most cases only small numbers of a few divisions.43 vitro from both EGF/FGF-2-expanded 27 such neurons emerge from these Thus, “pre-differentiation” of the ENPs and most of the genetically 53 manipulations, and thus the search con- ENPs prior to implantation would seem immortalised stem cell lines. However, tinues for a reliable culture method to logical and this approach has been when such cells are transplanted into the obtain sufficient numbers of dopaminer- adopted with some success by Studer myelin deficient environment, an in- gic neurons. and colleagues.44 An alternative ap- crease in oligodendroglial differentiation proach has been to employ ex vivo has been reported, which is associated TRANSPLANTATION OF NEURAL genetic techniques to modify cells prior with some myelination and in some 53 54 STEM CELLS FOR THE TREATMENT to implantation to express tyrosine hy- cases a degree of functional recovery. OF NEUROLOGICAL DISEASE droxylase, which again has met with The behaviour of embryonic NSCs fol- some success.45 APPLICATIONS OF NSCs AS lowing transplantation varies depending VECTORS FOR THE DELIVERY OF on the source of cell and animal model. Huntington’s disease BIOLOGICALLY ACTIVE In the case of human ENPs and the Transplantation repair in Huntington’s SUBSTANCES intact adult brain, it has been shown that disease provides different challenges for In addition to their potential to directly they are able to generate neurons in vivo ENPs, in that the transplanted cells must replace cells lost to disease and thereby in regions of active neurogenesis such as homotypically reconstruct circuitry. To reconstruct the CNS, NSCs might also 40 date, studies using NSCs in this disorder the SVZ and hippocampus, but not serve a role as efficient and flexible http://jnnp.bmj.com/ when placed in non-neurogenic areas are limited but there is some evidence of vectors for the sustained, local delivery of such as the striatum.41 The situation may appropriate neuronal differentiation neuroactive compounds to the brain—eg 46 be different in the diseased or damaged with human NSCs, although the func- neurotrophic factors for neuroprotec- CNS (see table 1). tional efficacy and connectivity of these tion, or to replace proteins lost because of cells in repairing the brain has not been single gene defects. In most envisioned Parkinson’s disease demonstrated. scenarios this would involve genetically Early transplant studies using human engineering the NSCs to direct, and Cerebral ischaemia ENPs showed some survival and regulate, the expression of therapeutic on September 30, 2021 by guest. Protected copyright. dopaminergic differentiation, but the Cell replacement therapy for ischaemic gene products (ex vivo gene therapy). numbers were low.42 This may relate to injury has experimentally shown some promise. For example, transplantation of Treatment of genetic disorders the MHP36 line (ReNeuron holdings) The aetiology of a number of rare, but Essential properties of stem cells has been reported to ameliorate cogni- devastating, inherited neurological con- for use in clinical transplantation tive deficits in rodent models of ditions can be fully attributed to the loss ischaemia.47 However, the applicability of of function of a single gene that encodes • Capable of clonal propagation in these findings to ENPs in general is for a metabolically or developmentally vitro to ensure homogeneity uncertain because other similarly critical enzyme. The ability of stem cells derived multipotential cell lines do not • Genetic stability at high passage to deliver functional enzymes diffusely show such an ability.48 hNT neurons in such neurogenetic degenerative con- • Integration within the host brain derived from a human teratocarcinoma ditions has been explored in some proto- following transplantation cell line have also been shown to typical animal models such as that for • Connectivity within host circuits alleviate motor and behavioural deficits mucopolysaccharidosis type VII (MPS • Migration and engraftment at sites of in animal models of ischaemia,49 al- VII, Morquio).55 damage though it is hard to attribute the • Correct differentiation into appro- functional recovery to circuit reconstruc- Neurotrophins and cytokines for priate neural cell types tion given the histological findings.50 neuroprotection • Functional benefits Nevertheless, some investigators have The understanding that the differentia- • Lack of side effects deemed this to be sufficient data to move tion and survival of neurons in develop- to a clinical trial in patients with basal ment is dependent on them receiving

www.jnnp.com J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.5.557 on 1 May 2003. Downloaded from 556 EDITORIAL adequate and specific trophic support Dohme. We apologise to all those whose work 20 Schwarz EJ, Alexander GM, Prockop DJ, et has meant that a number of cell delivery has not been cited because of space constraints. al. Multipotential marrow stromal cells transduced to produce L-DOPA: engraftment in systems have been examined, including J Neurol Neurosurg Psychiatry 2003;74:553– a rat model of Parkinson disease. Hum Gene NSCs. Such a delivery strategy is attrac- 557 Ther 1999;10:2539–49. tive compared to a viral vector based 21 Terskikh AV, Easterday MC, Li L, et al. From ...... hematopoiesis to neuropoiesis: evidence of delivery system because the host brain is overlapping genetic programs. Proc Natl not genetically manipulated, preventing Authors’ affiliations Acad Sci USA 2001;98:7934–9. insertional mutagenesis and preserving RABarker,MJain,RJEArmstrong, 22 Ramalho-Santos M, Yoon S, Matsuzaki Y, et M A Caldwell, Cambridge Centre for Brain al. “Stemness”: transcriptional profiling of the function of neurons in the host. In Repair, Forvie Site, Robinson Way, Cambridge embryonic and adult stem cells. Science addition, NSCs can be fully characterised CB2 2PY, UK 2002;298:597–600. such that the level of production of the 23 Ivanova NB, Dimos JT, Schaniel C, et al.A stem cell molecular signature. Science growth factor can be standardised, and, Correspondence to: R A Barker; [email protected] 2002;298:601–4. finally, extra safety features could be 24 Terada N, Hamazaki T, Oka M, et al. Bone incorporated, such as a “suicide cas- marrow cells adopt the phenotype of other REFERENCES cells by spontaneous cell fusion. 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Conversion disorder In summary, conversion disorder ap- ...... pears to be a disorder of affect regulation and symbolisation, in which somatic What is wrong in conversion disorder? experiencesandcomplaintsservetorepre- sent and convey emotional distress, a F Ovsiew purpose to which they are poorly suited...... Ideally, the management of these pati- ents centres on the formation of a treat- A disorder with many names ment relationship not to catch the patient out but to allow exploration of he article by Stone et al (this issue, p We have several clues about the areas of the patient’s life outside the pre- 591–596)1 addresses the natural his- fundamental nature of the disorder. senting symptoms and construction of a Ttory of a disorder with many names, Firstly, many of the patients have co- plan to reduce distress (including fo- none satisfactory. Functional, hysterical, existing organic brain disease. Secondly, cused treatment of commonly coexisting psychogenic, medically unexplained, dis- many have depressive disorders at the depressive disorder), and to develop sociative, conversion—all the names for time of presentation with medically alternative ways of seeking attention this disorder have their faults. Yet the unexplained somatic symptoms. These and assistance for distress. disorder is common, poses a manage- facts point to the possibility of disrup- http://jnnp.bmj.com/ ment problem for doctors, and carries a tion of personality function by brain dis- J Neurol Neurosurg Psychiatry 2003;74:557 poor prognosis. What is wrong with ease or by reversible abnormalities of these patients? brain state. Thirdly, however, many of the What is now clearly known not to be patients experienced sexual or physical ...... wrong is the occult presence of a neuro- abuse in childhood. This in itself, and as Author’s affiliation logical disorder. Several follow up stud- a proxy for widespread abnormality of F Ovsiew, Department of Psychiatry MC3077, University of Chicago, 5841 S. Maryland ies, this one included, show that the rate the childhood environment, indicates

Avenue, Chicago, IL 60637, USA; on September 30, 2021 by guest. Protected copyright. of erroneous diagnosis is low; neurologi- that developmental factors are com- cal disease is not being missed when [email protected] monly implicated in the personality dis- conversion disorder is diagnosed. Tech- turbance that gives rise (at times only niques of neurological examination that intermittently) to conversion symptoms allow recognition of non-organic mani- REFERENCES 2 as well as (often persistently) to other festations have been described, al- 1 Stone J, Sharpe M, Rothwell P, et al. The 12 4 As though patients with organic disease failures of psychosocial functioning. year prognosis of unilateral functional may—because of suggestibility and the is always the case with personality disor- weakness and sensory disturbance. J Neurol Neurosurg Psychiatry 2003;74:591–6. “demand characteristics” of the setting, der, heritable temperamental factors are likely to be relevant to vulnerability as 2 Stone J, Zeman A, Sharpe M. Functional generate non-organic signs if called on to 5 weakness and sensory disturbance. J Neurol do so by inappropriate examination.3 well. In addition, patients often adduce Neurosurg Psychiatry 2002;73:241–5. The follow up studies also show that the presence of contemporary “stress” in 3 Gould R, Miller BL, Goldberg MA, et al.The the origin of the symptoms. The evalua- validity of hysterical signs and symptoms. J most patients with conversion disorder NervMentDis1986;174:593–7. have persisting, or remitting and relaps- tor strains to discover the actual direc- 4 Meares R, Stevenson J, Gordon E. A ing, somatic symptoms. In addition, they tion of the causal arrow between person- Jacksonian and biopsychosocial hypothesis have impairment of psychological and ality dysfunction and chaotic or stressful concerning borderline and related phenomena. Aust N Z J Psychiatry social functioning outside the sphere of life events. In Cloninger’s words, “the 1999;33(6):831–40. medically unexplained somatic symp- development of a conversion or somati- 5 Cloninger CR. The origins of DSM and ICD toms. For example, they often have mood zation disorder occurs as part of a criteria for conversion and somatization disorders, self-injurious behaviour, dis- complex adaptive process involving non- disorders. In: Halligan PW, Bass C, Marshall JC, eds. Contemporary approaches to the sociative symptoms, and interpersonal linear interactions among multiple con- study of hysteria. Oxford: Oxford University difficulties. tributing factors”.5 Press, 2001:49–62.

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