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Annals of the New York Academy of Sciences 12/2006; 495(1):510 - 526. · 3.15 Impact Factor
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ABSTRACT: On the basis of animal studies, grafts of fetal human dopaminergic cells have been suggested as a therapy for Parkinson's disease. The purpose of this study was to characterize the ultrastructure and immunocytochemistry of human ventral mesencephalic xenografts placed into the catecholamine-depleted striata of athymic “nude” rats.Human fetal tissue was obtained from tissue fragments derived from elective abortions during the first trimester of pregnancy. Small pieces of the basal mesencephalon were grafted into the catecholamine-depleted striata of four athymic nude rats. The rats were allowed to survive from 3 to 6 months after grafting; following fixation, the striatal tissue containing the grafts was labeled with antibodies against tyrosine hydroxylase and serotonin.Immunocytochemistry revealed tyrosine-hydroxylase-like-immunoreactive (THLI) and serotoninlike-immunoreactive (5HTLI) cell bodies within the human grafts. Both 5HTLI and THLI fibers crossed the graft-host interface and innervated the previously lesioned striatum. Both types of fibers also entered the host cortex from the adjacent human graft.At the ultrastructural level, THLI and 5HTLI fibers and synaptic terminals were observed in the host neuropil. THLI and 5HTLI dendrites and axon terminals were also observed in the neuropil of the grafts themselves. THLI axon terminals are not normally present in the substantia nigra. The results of our study indicate that human xenografts can survive in the neuropil of the host striatum and form morphologically appropriate synapses within the host brain.
Synapse 10/2004; 4(1):19 - 29. · 2.94 Impact Factor
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ABSTRACT: Nerve growth factor promotes the survival of populations of sensory and sympathetic neurons. Although ganglia have been used for classical assays of neurotrophin action, knowledge is incomplete regarding the spatial arrangements through which neurotrophins are delivered to responsive cells within the ganglia and their attached nerve trunks. Whereas populations of ganglionic neurons may be capable of responding to a particular neurotrophin in vitro, the spectrum of receptor components and neurotrophins expressed by the various neuronal and nonneuronal cells comprising the ganglia in adult rats remains to be elucidated in vivo.Brain-derived neurotrophic factor (BDNF) mRNA was expressed by a population of small to medium sized neurons in all sensory ganglia except in the mesencephalic nucleus of the trigeminal nerve. Interestingly, BDNF immunoreactivity was detected in a more widespread population of neurons of these ganglia, as well as in scattered satellite cells of both sensory and sympathetic ganglia. These nonneuronal cells also expressed mRNA encoding a truncated form of the BDNF receptor, trkB trunc and full-length transcripts of trkB appeared to be confined to neuronal populations. Several other components of neurotrophin receptors (low-affinity neurotrophin receptor, trk, and trkC) were prominently expressed by different populations of neuronal cells in sympathetic and sensory ganglia, but they were not detected in nonneuronal cells. Neither nerve growth factor nor neurotrophin-3 mRNAs were detected in these ganglia.Unexpectedly, BDNF and trkB trunc expression was detected in oligodendrocytes myelinating the central processes of sensory neurons. Schwann cells did not express detectable quantities of either entity, thereby establishing a dramatic boundary delineated by neurotrophin/ neurotrophin receptor expression that coincided with the interface between the oligodendroglia of the central nervous system (CNS) and Schwann cells of the peripheral nervous system (PNS). Localization of BDNF expression to an additional population of nonneuronal cells—satellite cells within sensory and sympathetic ganglia—suggest a more extensive role for neurotrophic factors than originally encompassed by the target-derived neurotrophic-factorconcept paradigm. These data support the hypothesis of a possible autocrine or paracrine trophic interaction between populations of neuronal and nonneuronal cells in the peripheral nervous system. BDNF expression in oligodendrocytes but not in Schwann cells at the CNS/PNS junction may provide an additional means of maintaining cell-appropriate connections in the nervous system. © 1995 Wiley-Liss, Inc.
The Journal of Comparative Neurology 02/1995; 353(1):143 - 159. · 3.81 Impact Factor
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ABSTRACT: Two patients with advanced Parkinson's disease were followed for 6 months before, and 18 months after, receiving stereotaxic grafts of fetal mesencephalic tissue from aborted human fetuses. Parameters studied included a series of standardized tests of movement, response to levodopa, electrophysiological recording of the motor readiness potential, and positron emission tomography (PET) with ligands based upon levodopa and upon the dopamine reuptake inhibitor nomifensine. The patients each received stereotaxic implantation of ventral mesencephalic tissue containing midbrain dopamine neurons from aborted human fetuses of 8 to 10 weeks gestational age into the caudate and putamen of one hemisphere. Throughout their 18-month course, the patients were treated with cyclosporine, azathioprine, and glucocorticoids to minimize the risk of graft rejection. There were no significant complications from the procedure, but there was also no major change in their assessment of impairment on the Hoehn and Yahr scale. However, significant changes were observed in clinical, electrophysiological, and PET measures. Changes in these parameters, apparent at 6 months postoperatively, were described in detail in a previous report. The purpose of this present report is to provide follow-up data from the subsequent year with an emphasis on longitudinal evaluation methodology. Standardized clinical testing showed a small but long-term improvement in the first of the two patients. Following the operation, she was able to walk in “off” periods, which she had not been able to do preoperatively. This improvement was accompanied by increased walking speed and reduction in the time necessary to perform a series of pronation and supination movements using both hands. Although these improvements have continued throughout the postoperative period, they have not alleviated her basic neurological impairment. The second patient showed similar improvement during the first 6 months; she then reverted to her preoperative status at the end of the 18-month follow-up period. The electrophysiological recordings were consistent with the clinical findings. Both patients had significant changes in the motor readiness (bereitschafts) potential amplitude, which was greatest 5 to 7 months postoperation. The amplitude of the potential declined subsequently for both patients, but remained significantly elevated over the preoperative baseline for patient 1. The analysis of the PET scans was somewhat compromised by technical problems in the preoperative scans. However, they are also consistent with the clinical data. In comparisons of the operated and the unoperated sides, fluorodopa showed increased uptake in the caudate nucleus of patient 1 at 6 months and at 13 months. There was no increase for patient 2. Patient 2 showed an increase in nomifensine uptake over both the caudate and the putamen after 5 months, which declined at 12 months. The present follow-up of these two patients thus suggests that fetal mesencephalic grafts can have long-lasting effects in the brains of severely affected Parkinson's disease patients. Documentation of these effects requires longitudinal testing of a number of functional neurobiological parameters, however, since the grafts do not elicit a practical therapeutic benefit.
Experimental Neurology 01/1993; · 4.70 Impact Factor
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Ann-Charlotte Granholm,
Maria Eriksdotter-Nilsson,
Ingrid Strömberg,
Philip Stieg,
Åke Seiger,
Marc Bygdeman,
Michel Geffard,
Wolfgang Oertel,
Doris Dahl, Lars Olson,
Barry Hoffer,
Robert Freedman
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ABSTRACT: Human fetal hippocampal tissue from normal women was obtained following elective abortion in the 8th to the 11th week of gestation. The hippocampal tissue was transplanted to the anterior chamber of the eye of adult athymic nude rats, where it was allowed to develop for up to 9 months before histological and electrophysiological evaluation. The transplants were revascularized from the host iris and many grew extensively in oculo. Large neurons were present in all transplants. Immunohistochemical studies revealed glutamic acid decarboxylase-containing terminals and clusters of γ-aminobutyric acid-positive nerve cell bodies within the transplants, as well as scattered tyrosine hydroxylasepositive and acetylcholinesterase-containing fibers. Single neurons recorded extracellularly from transplants 4–9 months in oculo showed a slow spontaneous discharge, with both complex and single action potentials. Stimulation of the transplant surface evoked a small initial wave followed by a larger and longer-lasting field potential, similar to that seen in hippocampus in situ. A conditioning-testing paradigm was used to evaluate the presence of inhibitory circuitry in the hippocampal transplants. Significant suppression of the evoked test response was seen with interstimulus intervals ranging from 20 to 500 ms. Superfusion of enkephalin (100–300 nM) or penicillin (1600 U/ml) increased slow-wave activity, as did tetanic electrical stimulation. These treatments appeared to generate ictal-like activity, which in some cases persisted as interictal spikes. Illumination of the retina also increased neuronal activity, presumably by reflex activation of cholinergic afferents from the parasympathetic innervation of the iris. Taken together, our data suggest that fragments of hippocampus from aborted first trimester human fetuses, grafted to the eye chamber of rodent hosts, develop many organotypic histological and physiological features. This preparation may provide a unique means for the study of neurobiological properties of human brain in both normal and disease states.
Experimental Neurology 06/1989; · 4.70 Impact Factor
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ABSTRACT: Human fetal substantia nigra tissue, obtained following therapeutic termination of first trimester pregnancies, was grafted to cavities overlying the striatum in ciclosporin-treated rats whose nigrostriatal dopamine system had been removed unilaterally by 6-hydroxydopamine. Tyrosine hydroxylase (TH) immunocytochemistry revealed large numbers of surviving human substantia nigra neurons that matured and formed TH-positive nerve fibers reinnervating the host rat striatum. Apomorphine-induced rotational behavior in grafted animals was reduced by 70–80% in optimal cases 3–5 months after grafting. Thus human fetal dopamine neurons can correct functional deficits in dopamine-denervated rat hosts.
Neuroscience Letters 12/1986; · 2.11 Impact Factor
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ABSTRACT: The presence and morphology of GFA- and vimentin-positive astrocytes were studied immunohistochemically in rats using smear preparations of single intraocular grafts of the cortex cerebri anlage and of cortex pieces grafted to eyes containing a previously grafted piece of the locus coeruleus area. Similarly, astrocytes were studied in lesioned cortex cerebri in situ. A high number of GFA and vimentin-positive cells were found in smears of both types of cortex grafts as well as in smears of the lesioned cortex cerebri in situ. In contrast, only a limited number of GFA-positive astrocytes were seen in smears of normal cortex. Using computerized image analysis, the two-dimensional cell area and cell perimeter were found to be significantly increased in individual GFA-positive astrocytes in both types of intraocular cortex grafts as well as in the lesioned cortex when compared to GFA-positive astrocytes in normal cortex cerebri.GFA-positive cells in smears of cortex grafts from locus coeruleus-cortex combinations had significantly smaller cell area and cell perimeter values compared to similar cells from single cortex grafts. A similar, although less pronounced difference was observed between vimentin-positive cells from the same type of grafts. This suggests that the presence of the mature locus coeruleus graft in some as yet unknown way influences the development of the adjacent cortex graft towards a more normal astrocytic maturation. An additional finding was the large size difference between GFA- and vimentin-positive cells in the intraocular grafts. Since most evidence indicates that vimentin-positive cells are also GFA-positive, this may indicate that the two intermediate filament systems have a partially different distribution within individual astrocytes.It is concluded that computerized image analysis of smears processed for immunohistochemistry with antisera against GFA and vimentin is a useful technique for studies of astrocyte morphology in normal as well as experimentally perturbed CNS tissue. Cortex tissue that develops in contact with a locus coeruleus graft in the eye chamber show a significantly lesser degree of gliosis than cortex tissue developing in isolation in the eye.
International Journal of Developmental Neuroscience.
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ABSTRACT: To define the importance of adoptive sensitization and duration of graft residence on transplant alloimmunization, behavioral and histochemical parameters were examined in unilaterally 6-OHDA-lesioned F344 rat hosts which received fetal ventral mesencephalic (VM) grafts from Wistar-Furth (WF) donors. In all animals which showed increased rotations after alloimmunization, increased numbers of T cell receptor (TcR) positive, CD8+ lymphocytes were detected in the grafts. In addition, an increased density of class I MHC antigens was seen in the graft and in the adjacent host brain. Lesser numbers of CD4+, CD11b+, and MHCII+ positive elements were also seen. Perivascular cuffing was often found in actively immunized animals. An increase in TcR+ and MHC class I+ elements was also seen in animals only adoptively immunized. The tyrosine hydroxylase positive graft area was also markedly reduced in actively immunized animals and the extent of reduction correlated with the number of cells used for immunization. These studies indicate that established allografts can evade rejection as long as host lymphocytes are not activated against graft alloantigens. In addition, increasing graft residence time in the host and adoptive immunization render the graft more susceptible to subsequent rejection.
Brain Research.
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ABSTRACT: Pieces of the immature hippocampal formation were transplanted to the anterior chamber of adult rat eyes. The transplants survived, became vascularized from the host irides, and proliferated extensively in proportion to the age of the donor fetus. These transplants mature and develop an adult organization in oculo. This maturation proceeds unimpaired in the absence of gyrus dentatus or after superior cervical ganglionectomy.The various strata of normal hippocampus could be readily identified cytologically in the transplants. Surface electrical stimulation elicited negative and positive field potentials at various depths in the transplant. These potentials could be associated with excitation and inhibition of pyramidal neurons respectively. Much of the excitation could be shown to be orthodromic in nature. In contrast to in situ findings, however, pyramidal cells in oculo had negligible spontaneous activity.It is concluded that the local excitatory and inhibitory pathways in hippocampus develop in the absence of any extrahippocampal afferents. Moreover, the overall high degree of cytological and electrophysiological organization suggests that many of the regulatory factors in hippocampal maturation are intrinsic and do not require extrahippocampal neural input.
Brain Research.
