Transplanted neuronal precursors migrate and differentiate in the developing mouse brain.
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The subventricular zone (SVZ), lining the lateral ventricle in forebrain, retains a population of neuronal precursors with the ability of proliferation in adult mammals. To test the potential of neuronal precursors in adult mice, we transplanted adult SVZ cells labeled with fluorescent dye PKH26 into the lateral ventricle of the mouse brain in different development stages. The preliminary results indicated that the grafted cells were able to survive and migrate into multiple regions of the recipient brain, including SVZ, the third ventricle, thalamus, superior colliculus, inferior colliculus, cerebellum and olfactory bulb etc; and the amount of survival cells in different brain regions was correlated with the development stage of the recipient brain. Immunohistochemical studies showed that most of the grafted cells migrating into the specific target could express neuronal or astrocytic marker. Our results revealed that the neuronal precursors in adult SVZ still retained immortality and ability of proliferation, which is likely to be induced by some environmental factors. (+info)
Sham surgery controls: intracerebral grafting of fetal tissue for Parkinson's disease and proposed criteria for use of sham surgery controls.
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Sham surgery is a controversial and rarely used component of randomised clinical trials evaluating surgical interventions. The recent use of sham surgery in trials evaluating efficacy of intracerebral fetal tissue grafts in Parkinson's disease has highlighted the ethical concerns associated with sham surgery controls. Macklin, and Dekkers and Boer argue vigorously against use of sham surgery controls. Macklin presents a broad argument against sham surgery controls while Dekkers and Boer present a narrower argument that sham surgery is unnecessary in the specific setting of fetal tissue engraftment for Parkinson's disease. I defend sham surgery controls against both these criticisms. Appropriate clinical trial design, sometimes including sham surgery, is needed to ensure that false positive trial results do not occur and endanger public safety. Results of a completed trial of fetal tissue grafting for Parkinson's disease are used to illustrate the potential benefits of, and problems associated with, sham surgery controls. Sham surgery controls, however, should be employed only when absolutely necessary. I suggest criteria for appropriate use of sham surgery controls. (+info)
Neural stem cells: progression of basic research and perspective for clinical application.
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It has long been thought that functional regeneration of the injured central nervous system (CNS) is impossible, as Santiago Ramony Cajal described in the early 20th century, "once the development was ended, the fonts of growth and regeneration ... dried up irrevocably". In mammalian neural development, most neuronal production (neurogenesis) occurs in the embryonic stage. However, recent findings indicate that neurogenesis continues in the olfactory bulb, hippocampus, and dentate gyrus of adult mammalian animals, from the neural stem cells (NSCs). Recently developed techniques have made it possible to isolate, culture, and grow pluripotent self-renewing NSCs from both embryonic and adult brains. This basic research is attracting a lot of attention because of the hope that it will lead to regeneration and reconstruction therapy for the damaged CNS. In this review, recent findings on the stem cell biology of the CNS and strategies for its potential therapeutic application will be discussed. (+info)
The use of foetal human brain tissue as brain implants: phenotype manipulation by genetic manipulation and biochemical induction.
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The use of dopaminergic mesencephalic (VM) human foetal brain tissue as implants to neurosurgically treat Parkinson's disease has been in progress since the 1980's. A major limitation in the use of VM tissue is the amount of tissue available from each human embryo. Usually tissue from about 7 embryos is required to treat each patient unilaterally. To overcome this we have developed various strategies. One is to convert embryonic cerebral cortex in human embryos into dopaminergic tissue which is stable, and which will secrete dopamine in vivo once implanted. The cerebral cortex is about 500 times larger than the VM and can therefore provide a lot more tissue for transplantation. This can be achieved by genetic manipulation of the embryonic cerebral cortex tissue, involving the lipo-transfection of multiple copies of the human tyrosine hydroxylase gene into both neurones and glial cells. In another approach we have biochemically manipulated the development of the cerebral cortex to direct the neurotransmitter phenotype towards the dopaminergic type, and away from other phenotypes. This tissue, too, is stable and will synthesise and secrete dopamine when transplanted. Our third approach has been to manipulate pluripotential neural cells which are yet to develop into neurones and glial cells. These cells can be expanded in number many-fold before treatment to direct their development into stable dopaminergic neurones in large numbers (70%), which synthesise and release dopamine. When used as transplants in animal models of Parkinson's disease, these various types of artificially induced dopaminergic tissue are very effective at reducing the Parkinsonian syndrome. (+info)
Unilateral transplantation of human primary fetal tissue in four patients with Huntington's disease: NEST-UK safety report ISRCTN no 36485475.
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OBJECTIVES: Huntington's disease (HD) is an inherited autosomal dominant condition in which there is a CAG repeat expansion in the huntingtin gene of 36 or more. Patients display progressive motor, cognitive, and behavioural deterioration associated with progressive cell loss and atrophy in the striatum. Currently there are no disease modifying treatments and current symptomatic treatments are only partially effective in the early to moderate stages. Neural transplantation is effective in animal models of HD and offers a potential strategy for brain repair in patients. The authors report a safety study of unilateral transplantation of human fetal striatal tissue into the striatum of four patients with HD. SUBJECTS AND METHODS: Stereotaxic placements of cell suspensions of human fetal ganglionic eminence were made unilaterally into the striatum of four patients with early to moderate HD. All patients received immunotherapy with cyclosporin A, azathioprine, and prednisolone for at least six months postoperatively. Patients were assessed for safety of the procedure using magnetic resonance imaging (MRI), regular recording of serum biochemistry and haematology to monitor immunotherapy, and clinical assessment according to the Core Assessment Protocol For Intrastriatal Transplantation in HD (CAPIT-HD). RESULTS: During the six month post-transplantation period, the only adverse events related to the procedure were associated with the immunotherapy. MRI demonstrated tissue at the site of implantation, but there was no sign of tissue overgrowth. Furthermore, there was no evidence that the procedure accelerated the course of the disease. CONCLUSIONS: Unilateral transplantation of human fetal striatal tissue in patients with HD is safe and feasible. Assessment of efficacy will require longer follow up in a larger number of patients. (+info)
Recovery from lesion-associated learning deficits by fetal amygdala transplants.
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Bilateral lesions of the amygdaloid complex result in elimination or attenuation of the conditioned freezing that is normally seen in the conditioned emotional response (CER) paradigm and the active avoidance (AA) task. We observed the effect of amygdalar tissue transplantation on the ability of lesioned (central nucleus of amygdala, CeA) rats to learn CER and AA. In two groups of adult Wistar rats, sham operation or bilateral lesions of the CeA were produced electrolytically (2mA for 8 sec). In a third group, fetal amygdalar tissue was transplanted at the CeA-lesioned site 2 d postoperatively. All rats were trained on CER and AA from the 6th postoperative day. In comparison with the sham-operated group, bilaterally CeA-lesioned rats showed a significant (p < 0.001) increase in all CER scores, indicating an acquisition deficit. After fetal amygdalar tissue transplantation, the CER scores significantly decreased (p < 0.05) when compared with the lesioned group. A significant (p < 0.01) decrease in the percentage of avoidance in the AA task occurring after CeA lesion returned to control values after amygdalar tissue transplantation. In conclusion, in CeA-lesioned rats a complete behavioral deficit in learning CER and AA was restored by transplanting fetal amygdalar tissue at the lesioned site. (+info)
Ectopic transplantation of the accessory medulla restores circadian locomotor rhythms in arrhythmic cockroaches (Leucophaea maderae).
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The presence of an endogenous circadian clock in the brain of an animal was first demonstrated in the cockroach Leucophaea maderae. However, the clock's cellular basis remained elusive until pigment-dispersing hormone-immunoreactive neurons, which express the clock genes period and timeless in Drosophila, were proposed as pacemaker candidates. In several insect species, pigment-dispersing hormone-immunoreactive neurons are closely associated with the accessory medulla, a small neuropil in the optic lobe, which was suggested to be a circadian clock neuropil. Here, we demonstrate that ectopic transplantation of adult accessory medulla into optic lobe-less cockroaches restores circadian locomotor activity rhythms in L. maderae. All histologically examined cockroaches that regained circadian activity regenerated pigment-dispersing hormone-immunoreactive fibres from the grafts to original targets in the protocerebrum. The data show that the accessory medulla is the circadian pacemaker controlling locomotor activity rhythms in the cockroach. Whether pigment-dispersing hormone-immunoreactive neurons are the only circadian pacemaker cells controlling locomotor activity rhythms remains to be examined. (+info)
Somatic motoneurone specification in the hindbrain: the influence of somite-derived signals, retinoic acid and Hoxa3.
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We have investigated the mechanisms involved in generating hindbrain motoneurone subtypes, focusing on somatic motoneurones, which are confined to the caudal hindbrain within rhombomeres 5-8. Following heterotopic transplantation of rhombomeres along the rostrocaudal axis at various developmental stages, we have found that the capacity of rhombomeres to generate somatic motoneurones is labile at the neural plate stage but becomes fixed just after neural tube closure, at stage 10-11. Grafting of somites or retinoic acid-loaded beads beneath the rostral hindbrain induced the formation of somatic motoneurones in rhombomere 4 only, and Hox genes normally expressed more caudally (Hoxa3, Hoxd4) were induced in this region. Targeted overexpression of Hoxa3 in the rostral hindbrain led to the generation of ectopic somatic motoneurones in ventral rhombomeres 1-4, and was accompanied by the repression of the dorsoventral patterning gene Irx3. Taken together, these observations suggest that the somites, retinoic acid and Hox genes play a role in patterning somatic motoneurones in vivo. (+info)