Polysialylated neural cell adhesion molecule-positive CNS precursors generate both oligodendrocytes and Schwann cells to remyelinate the CNS after transplantation.
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Transplantation offers a means of identifying the differentiation and myelination potential of early neural precursors, features relevant to myelin regeneration in demyelinating diseases. In the postnatal rat brain, precursor cells expressing the polysialylated (PSA) form of the neural cell adhesion molecule NCAM have been shown to generate mostly oligodendrocytes and astrocytes in vitro (Ben-Hur et al., 1998). Immunoselected PSA-NCAM+ newborn rat CNS precursors were expanded as clusters with FGF2 and grafted into a focal demyelinating lesion in adult rat spinal cord. We show that these neural precursors can completely remyelinate such CNS lesions. While PSA-NCAM+ precursor clusters contain rare P75+ putative neural crest precursors, they do not generate Schwann cells in vitro even in the presence of glial growth factor. Yet they generate oligodendrocytes, astrocytes, and Schwann cells in vivo when confronted with demyelinated axons in a glia-free area. We confirmed the transplant origin of these Schwann cells using Y chromosome in situ hybridization and immunostaining for the peripheral myelin protein P0 of tissue from female rats that had been grafted with male cell clusters. The number and distribution of Schwann cells within remyelinated tissue, and the absence of P0 mRNAs in donor cells, indicated that Schwann cells were generated by expansion and differentiation of transplanted PSA-NCAM+ neural precursors and were not derived from contaminating Schwann cells. Thus, transplantation into demyelinated CNS tissue reveals an unexpected differentiation potential of a neural precursor, resulting in remyelination of CNS axons by PNS and CNS myelin-forming cells. (+info)
Associative plasticity in striatal transplants.
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Striatal lesions disrupt both motor and cognitive performance in rats, many aspects of which can be restored by striatal transplants. Because the normal striatum is involved in the formation and maintenance of motor habits, it has been hypothesized that grafted animals may require explicit retraining to relearn previously established habits that have been disrupted by the lesions. We have used a lateralized-discrimination task to reproduce this "learning to use the transplant" effect, combined with a transfer-of-training paradigm to demonstrate that recovery requires relearning specific lateralized stimulus-response associations and cannot be explained simply by a generalized training-dependent improvement in motor skill. These results have clear implications for developing appropriate strategies for the rehabilitation of Huntington's disease patients participating in clinical transplantation programs. (+info)
Prospects for the clinical application of neural transplantation with the use of conditionally immortalized neuroepithelial stem cells.
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Although neural transplantation has made a relatively successful transition from the animal laboratory to human neurosurgery for the treatment of Parkinson's disease, the use of human embryonic brain tissue as the source of transplants raises difficult ethical and practical problems. These are likely to impede the widespread use of this otherwise promising therapy across the range of types of brain damage to which the results of animal experiments suggest its potential applicability. Various alternative approaches are reviewed briefly, aimed at developing sources of tissue for transplantation that can be maintained in vitro until needed, so obviating the requirement for fresh embryonic tissue at each occasion of surgery. Particularly promising are conditionally immortalized neuroepithelial stem cell lines in which the immortalizing gene is downregulated upon transplantation into a host brain. We describe experiments from our laboratory with the use of cells of this kind, the multipotent MHP clonal cell lines, derived from the developing hippocampus of a transgenic mouse harbouring a temperature-sensitive oncogene. Implanted into the hippocampus of rats and marmosets with damage to the CA1 cell field, the MHP36 line gave rise to healthy surviving grafts and to essentially complete recovery of cognitive function. Postmortem study of the implanted rat brains indicated that MHP36 cells migrate to the region of damage, adopt both neuronal (pyramidal) and glial phenotypes in vivo, and reconstitute the normal laminated appearance of the CA1 cell field. We have previously shown that, when primary differentiated foetal tissue is used as the source of grafts in rats with CA1 damage, there is a stringent requirement for replacement with homotypic CA1 cells. We interpret our results as showing that the MHP36 cell line responds to putative signals associated with damage to the hippocampus and takes up a phenotype appropriate for the repair of this damage; they therefore open the way to the development of a novel strategy with widespread applicability to the treatment of the diseased or damaged human brain. (+info)
Promoter-activated expression of nerve growth factor for treatment of neurodegenerative diseases.
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Genetic transfer approaches have received recent consideration as potential treatment modalities for human central and peripheral nervous system (CNS and PNS, respectively) neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Transplantation of genetically modified cells into the brain represents a promising strategy for the delivery and expression of specific neurotrophic factors, neurotransmitter-synthesizing enzymes, and cellular regulatory proteins for intervention in neurodegenerative diseases. The use of specific regulatable promoters may also provide potential control of gene expression required for dose-specific or time-specific therapeutic strategies. In this article, we review the potential use of activated promoters in ex vivo systems for the potential genetic therapy of neurodegenerative disorders, and then describe our own studies using the zinc-inducible metallothionein promoter for the regulated expression of nerve growth factor (NGF) in rodent brain transplants. (+info)
Fine structure of host-graft relationships between transplanted chromaffin cells and CNS.
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Our laboratory studies have shown that transplantation of adrenal medullary tissue or isolated chromaffin cells into central nervous system (CNS) pain modulatory regions (i.e., periaqueductal gray and subarachnoid lumbar spinal cord) can reduce pain sensitivity of rats in both acute and chronic pain. The analgesia produced by these transplants is thought to result from release of both opiate peptides and catecholamines. Morphologically, these animal studies also suggest that there is no development of tolerance over long periods of time, and the transplanted chromaffin cells appear to be robust and well integrated with the host tissue. In our initial clinical studies, where allografts of adrenal medullary tissue were transplanted intrathecally to relieve intractable cancer pain, patients obtained significant and long-lasting pain relief. Increased cerebrospinal fluid (CSF) levels of metenkephalin were correlated with the decreased pain scores. Histology of autopsy tissue obtained from two patients with 1 year transplants revealed viable transplanted chromaffin cells. Because of the limited availability of human adrenal glands, sources of xenogeneic chromaffin cells will need to be identified if effective transplantation therapy for chronic pain is to be developed further. (+info)
Gene therapy for chronic relapsing experimental allergic encephalomyelitis using cells expressing a novel soluble p75 dimeric TNF receptor.
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In a murine relapsing experimental allergic encephalomyelitis (EAE) model, gene therapy to block TNF was investigated with the use of a retroviral dimeric p75 TNF receptor (dTNFR) construct. To effectively produce these TNF inhibitors in vivo, a conditionally immortalized syngeneic fibroblast line was established, using a temperature-sensitive SV40 large T Ag-expressing retrovirus. These cells were subsequently infected with a retrovirus expressing soluble dTNFR. CNS-injected cells could be detected 3 mo after transplantation and were shown to produce the transgene product by immunocytochemistry and ELISA of tissue fluids. These levels of dTNFR protein were biologically active and could significantly ameliorate both acute and relapsing EAE. This cell-based gene-vector approach is ideal for delivering proteins to the CNS and has particular relevance to the control of inflammatory CNS disease. (+info)
Surgical treatments for Parkinson's disease.
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OBJECTIVE: This article reviews surgical treatments for Parkinson's disease, emphasizing aspects pertinent to family physicians: rationale for and description of surgeries, patient selection issues, and outcome expectations. QUALITY OF EVIDENCE: No published series describes long-term follow up of a randomized controlled study of any surgery for Parkinson's disease. Some reports, however, describe thorough but brief follow up of functioning in small numbers of patients following surgery. MEDLINE articles were identified using Parkinson's disease, surgery, pallidotomy, thalamotomy, stimulation, grafting, and transplantation as search words. Articles chosen for this paper described patients with systematic follow up using accepted validated rating scales. MAIN MESSAGE: Reported series show impressive improvements to patients undergoing lesioning, stimulation, and grafting surgery for Parkinson's disease. These patients are typically severely disabled but highly selected, and follow up is brief. Stereotactic lesioning (pallidotomy and thalamotomy), deep brain stimulation (thalamic, and elsewhere) and grafting (striatal) can be performed safely, but results vary greatly among centres. CONCLUSIONS: Certain Parkinson's disease patients might benefit from surgery. Ideal candidates for pallidotomy experience motor fluctuations with disabling levodopa-induced dyskinesias. Tremors resistant to antiparkinsonian medications sometimes respond to thalamotomy or thalamic stimulation. Other parkinsonian syndromes, dementias, and difficulties with gait and balance respond poorly to unilateral pallidotomy. Bilateral deep brain stimulation procedures could benefit "midline" dysfunction. (+info)
Intracerebral transplants and memory dysfunction: circuitry repair or functional level setting?
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Intracerebral grafting techniques of fetal neural cells have been used essentially with two main types of lesion paradigms, namely damage to long projection systems, in which the source and the target are clearly separate, and damage to neurons that are involved in local circuits within a small (sub)region of the brain. With the first lesion paradigm, grafts placed homotopically (in the source) are not appropriate because their fibers grow poorly through the host parenchyma and fail to reach their normal target. To be successful, the grafts must be placed ectopically in the target region of the damaged projection systems, where generally they work as level-setting systems. Conversely, with the second paradigm, the grafts are supposed to compensate for a local loss of neurons and must be placed homotopically to induce functional effects that are based on the reconstruction of a point-to-point circuitry. By inserting a biological or artificial bridging-substrate between the source and the target of long projection systems, it might be possible to combine the positive effects of both homotopic and ectopic grafting by achieving both target reinnervation and normal control of the grafted neurons within the source area. These issues are illustrated and discussed in this review. (+info)