Effects of Glial Cell Line-Derived Neurotrophic Factor on Developing and Mature Ventral Mesencephalic Grafts in Oculo

Johansson, Maria H.; Friedemann, M; Hoffer, Barry J.; Strömberg, Ingrid

doi:10.1006/exnr.1995.1033

Cited by 73 publications

(39 citation statements)

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“…from diffuse and sparse to dense and patchy (Törnqvist et al, 2000). However, GDNF treatment of mature dopamine grafts did not affect survival and outgrowth from grafted dopamine neurons (Johansson et al, 1995;Winkler et al, 2006), but enhanced nerve fiber formation within the grafts, a phenomenon also found using other factors . This phenomenon may cause reduced graft function since high dopamine activity surrounding the grafted dopamine neurons should, theoretically, shut down neuronal activity for the dopamine neurons that target the host striatum, thus reducing dopamine release in the host target.…”

Section: Introductionmentioning

confidence: 74%

Effects of glial cell line-derived neurotrophic factor deletion on ventral mesencephalic organotypic tissue cultures

et al. 2007

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Glial cell line-derived neurotrophic factor (GDNF) is potent for survival and promotion of nerve fibers from midbrain dopamine neurons. It is also known to exert different effects on specific subpopulations of dopamine neurons. In organotypic tissue cultures, dopamine neurons form two diverse nerve fiber growth patterns, targeting the striatum differently. The aim of this study was to investigate the effect of GDNF on the formation of dopamine nerve fibers. Organotypic tissue cultures of ventral mesencephalon of gdnf gene-deleted mice were studied. The results revealed that dopamine neurons survive in the absence of GDNF. Tyrosine hydroxylase immunoreactivity demonstrated, in gdnf knockout and wildtype cultures, nerve fiber formation with two separate morphologies occurring either in the absence or the presence of astrocytes. The outgrowth that occurred in the absence of astrocytes was unaffected by gdnf deletion, whereas nerve fibers guided by the presence of astrocytes were affected in that they reached significantly shorter distances from the gdnf gene-deleted tissue slice, compared to those measured in wildtype cultures. Treatment with GDNF reversed this effect and increased nerve fiber density independent of genotype. Furthermore, migration of astrocytes reached significantly shorter distances from the tissue slice in GDNF knockout compared to wildtype cultures. Exogenous GDNF increased astrocytic migration in gdnf gene-deleted tissue cultures, comparable to lengths observed in wildtype tissue cultures. In conclusion, cultured midbrain dopamine neurons survive in the absence of GDNF, and the addition of GDNF improved dopamine nerve fiber formation -possibly as an indirect effect of astrocytic stimulation.

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Section: Introductionmentioning

confidence: 74%

Effects of glial cell line-derived neurotrophic factor deletion on ventral mesencephalic organotypic tissue cultures

et al. 2007

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“…Since a large window for improvement exists with regard to graft viability and neurite outgrowth, transplants may be able to provide even greater benefit to patients with PD following further refinement of this procedure. Toward this end, trophic factors and trophic factor-secreting cells have been shown to augment the viability and functional benefits of fetal nigral grafts (Sauer et al, 1993;Johansson et al, 1995;Takayama et al, 1995;Yurek et al, 1996). It has recently been demonstrated that treatment of fetal rodent nigral cells with antioxidents (Nakao et al, 1995) or lazeroids (Nakao et al, 1994) augments their viability following grafting as well.…”

Section: Dmentioning

confidence: 95%

Functional fetal nigral grafts in a patient with Parkinson's disease: Chemoanatomic, ultrastructural, and metabolic studies

et al. 1996

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A patient with Parkinson's disease received bilateral fetal human nigral implants from six donors aged 6.5 to 9 weeks post-conception. Eighteen months following a post-operative clinical course characterized by marked improvement in clinical function, this patient died from events unrelated to the grafting procedure. Post-mortem histological analyses revealed the presence of viable grafts in all 12 implant sites, each containing a heterogeneous population of neurons and glia. Approximately 210,146 implanted tyrosine hydroxylase-immunoreactive (TH-ir) neurons were found. A greater number of TH-ir grafted neurons were observed in the right (128,162) than the left (81,905) putamen. Grafted TH-ir neurons were organized in an organotypic fashion. These cells provided extensive TH-ir and dopamine transporter-ir innervation to the host striatum which occurred in a patch-matrix fashion. Quantitative evaluations revealed that fetal nigral grafts reinnervated 53% and 28% of the post-commissural putamen on the right and left side, respectively. Grafts on the left side innervated a lesser area of the striatum, but optical density measurements were similar on both sides. There was no evidence that the implants induced sprouting of host TH-ir systems. Electron microscopic analyses revealed axo-dendritic and occasional axo-axonic synapses between graft and host. In contrast, axo-somatic synapses were not observed. In situ hybridization for TH mRNA revealed intensely hybridized grafted neurons which far exceeded TH mRNA expression within residual host nigral cells. In addition, gamma-amino butyric acid (GABA)-ergic neurons were observed within the graft that formed a dense local neuropil which was confined to the implant site. Serotonergic neurons were not observed within the graft. Cytochrome oxidase activity was increased bilaterally within the grafted post-commissural putamen, suggesting increased metabolic activity. In this regard, a doubling of cytochrome oxidase activity was observed within the grafted post-commissural putamen bilaterally relative to the non-grafted anterior putamen. The grafts were hypovascular relative to the surrounding striatum and host substantia nigra. Blood vessels within the graft stained intensely for GLUT-1, suggesting that this marker of blood--brain barrier function is present within human nigral allografts. Taken together, these data indicate that fetal nigral neurons can survive transplantation, functionally reinnervate the host putamen, establish synaptic contacts with host neurons, and sustain many of the morphological and functional characteristics of normal nigral neurons following grafting into a patient with PD.

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“…However, it is a large protein and has to be delivered directly to the brain rather than given peripherally. When this is done, GDNF can support the survival and outgrowth of DA neurons following transplantation (Johansson et al, 1995). In addition, GDNF added to cell suspensions of embryonic ventral mesencephalic (VM) tissue improves the survival of DA neurons following grafting into the denervated striatum (Apostolides et al, 1998;Mehta et al, 1998;Sullivan et al, 1998).…”

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confidence: 99%

Neurospheres modified to produce glial cell line‐derived neurotrophic factor increase the survival of transplanted dopamine neurons

Ostenfeld

Tai

Martin

et al. 2002

J of Neuroscience Research

122

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Glial cell line-derived neurotrophic factor (GDNF) has been shown to increase the survival of dopamine neurons in a variety of in vitro and in vivo model systems. Therefore, it constitutes an important therapeutic protein with the potential to ameliorate dopamine neuronal degeneration in Parkinson's disease or to support dopamine neuronal replacement strategies. However, biophysical and practical considerations present obstacles for the direct delivery of the GDNF protein to CNS neurons. Here we show that rodent neural precursor cells isolated and expanded in culture as neurospheres (NS) can be genetically modified to express green fluorescent protein (GFP) or to release GDNF using lentiviral constructs. GDNF-NS increased the fibre outgrowth of primary embryonic dopamine neurons in cocultures, showing that the protein was released in biologically significant quantities. Furthermore, after transplantation into the 6-hydroxydopamine-lesioned rat striatum, GDNF-NS significantly increased the survival of cografted primary dopamine neurons. However, this was not reflected in behavioural recovery in these animals. We found that, by 6 weeks, few cells expressed GDNF or GFP, suggesting either that transgene expression was down-regulated over time or that the cells died. This may explain the initial effects on dopamine neuronal survival within the graft but the lack of long-term effect on subsequent fibre outgrowth and behaviour. Providing sustained levels of neural precursor-mediated transgene expression can be achieved following transplantation in the future; this approach may prove beneficial as an alternative therapeutic strategy in the cell-based management of Parkinson's disease.

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Effects of Glial Cell Line-Derived Neurotrophic Factor on Developing and Mature Ventral Mesencephalic Grafts in Oculo

Cited by 73 publications

References 0 publications

Effects of glial cell line-derived neurotrophic factor deletion on ventral mesencephalic organotypic tissue cultures

Effects of glial cell line-derived neurotrophic factor deletion on ventral mesencephalic organotypic tissue cultures

Functional fetal nigral grafts in a patient with Parkinson's disease: Chemoanatomic, ultrastructural, and metabolic studies

Neurospheres modified to produce glial cell line‐derived neurotrophic factor increase the survival of transplanted dopamine neurons

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