Transplants of purified astrocytes promote behavioral recovery after frontal cortex ablation

Kesslak, J. Patrick; Nieto–Sampedro, Manuel; Globus, Joseph H.; Cotman, Carl W.

doi:10.1016/0014-4886(86)90089-0

Cited by 206 publications

(38 citation statements)

References 11 publications

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“…In other experiments, a nitrocellulose filter embedded with early postnatal astrocytes and implanted into previously acallosal mice provided a terrain suitable for axons to traverse the cerebral midline to reform a corpus callosum (Silver and Ogawa, 1983;Smith et al, 1986). The implantation of astrocytes into adult rats with CNS lesions has resulted in the recovery of T-maze learning behavior (Kesslak et al, 1986;Bradbury et al, 1995) and an increase in the intensity of neurofilament labeling at the lesion site (Wang et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…The stab site, shown in the right panels, is seen as an indentation in the outer surface of the cortex. tracts collected from around CNS lesion sites support the survival and growth of neurons in vitro (Nieto-Sampedro et al, 1982Kesslak et al, 1986;Needels et al, 1986). Although Ip et al (1993) demonstrated that a candidate neurotrophic factor in these injury extracts is ciliary neurotrophic factor, it remains to be assessed systematically whether and to what degree inflammatory cytokines contribute to the neurotrophic activity that is found in injury extracts.…”

Section: Table 2 Extent Of Astrogliosis In Cd1 Adult Mouse Brain Trementioning

confidence: 99%

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Astrogliosis in the Neonatal and Adult Murine Brain Post-Trauma: Elevation of Inflammatory Cytokines and the Lack of Requirement for Endogenous Interferon-γ

et al. 1997

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The relevance of astrogliosis remains controversial, especially with respect to the beneficial or detrimental influence of reactive astrocytes on CNS recovery. This dichotomy can be resolved if the mediators of astrogliosis are identified. We have measured the levels of transcripts encoding inflammatory cytokines in injury systems in which the presence or absence of astrogliosis could be produced selectively. A stab injury to the adult mouse brain using a piece of nitrocellulose (NC) membrane elicited a prompt and marked increase in levels of transcripts for interleukin (IL)-1α, IL-1β, and tumor necrosis factor (TNF)-α, which are considered to be microglia/macrophage cytokines. The elevations preceded, or occurred concomitantly with, the rise in glial fibrillary acidic protein mRNA, an early manifestation of astrogliosis. In neonatal mice, IL-1 and TNF-α mRNA were elevated to a greater extent by an NC-implant injury, which produced astrogliosis, than after an NC-stab, with minimal astrogliosis. We determined whether endogenous interferon (IFN)-γ could be responsible for the observed increases in IL-1 and TNF-α, because IFN-γ is a potent microglia/macrophage activator, and because its exogenous administration to rodents enhanced astrogliosis after adult or neonatal insults. A lack of requirement for endogenous IFN-γ was demonstrated by three lines of evidence. First, no increase in IFN-γ transcripts could be found at injury. Second, the administration of a neutralizing antibody to IFN-γ did not attenuate astrogliosis. Third, in IFN-γ knockout adult mice, astrogliosis and increases in levels of IL-1α and TNF-α were induced rapidly by injury. The marked elevation of inflammatory cytokines is discussed in the context of astrogliosis and general CNS recovery.

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Section: Discussionmentioning

confidence: 99%

Section: Table 2 Extent Of Astrogliosis In Cd1 Adult Mouse Brain Trementioning

confidence: 99%

Astrogliosis in the Neonatal and Adult Murine Brain Post-Trauma: Elevation of Inflammatory Cytokines and the Lack of Requirement for Endogenous Interferon-γ

et al. 1997

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“…Although the trophic graft mechanisms in other transplant models may account for some graft effects (38)(39)(40), available rodent models of HD show that the implanted striatal neurons can substitute for the damaged striato-pallidal neuronal connections (23)(24)(25)(26)(27). Physiological (15)(16)(17), neurochemical (41,42), and anatomical studies (23)(24)(25)(26)(27) suggest that a partial restoration of striatal input and output circuitry by implanted striatal neurons can occur.…”

Section: Discussionmentioning

confidence: 99%

Intrastriatal transplantation of cross-species fetal striatal cells reduces abnormal movements in a primate model of Huntington disease.

Hantraye

Riché

Mazière

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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Huntington disease is a neurological movement disorder involving massive neuronal death in the caudate-putamen region of the brain. Neither preventive nor curative therapy exists for this disease. The implantation of cross-species striatal neural precursor cells into the lesioned striatum of nonhuman primates (baboons) reduced the abnormal movements seen in the disease model. These abnormal movements reappeared after immunological rejection of the implanted striatal cells and were not modified by transplantation with nonstriatal cells. These findings encourage further experimentation toward the use of cell sources other than human fetal cells in a potential clinical application to Huntington disease.Huntington disease (HD) evolves over several years with a continuous deterioration of the patient's condition. The motor and cognitive symptoms are associated with neuronal loss in the caudate-putamen, cerebral cortex, globus pallidus, and substantia nigra (1-5). The neuropathological changes in HD are dominated by the severe atrophy, neuronal cell loss, and astrocytic reaction in the caudate-putamen complex (striatum). By intrastriatal application of the neurotoxin ibotenic acid (IA), we have created a striatal pathology similar to HD in the baboon to evaluate therapeutic strategies, such as neuronal implantation (6). Intrastriatal injections of the glutamate receptor agonist IA and other glutamate agonists cause severe neuronal loss of striatal output neurons but spare axons of passage and striatal afferents, a characteristic pathological feature of HD (6-10). The many neuropathological and neurochemical similarities between such striatal lesions in the rat brain and alterations found in the brain of choreic patients have suggested a role for glutamate receptor agonists in the neurodegenerative mechanisms underlying HD (8,(10)(11)(12). Previous studies have utilized intrastriatal injections of IA, quinolinic, or kainic acid to produce a primate model of HD (6,13,14). Whatever the toxin used, the primates receiving such striatal lesions all display a variety of abnormal movements similar to the symptoms observed in HD patients, including dyskinesia, orofacial dyskinesia, chorea, and dystonia. These findings contrast sharply with previous rat models where involuntary choreiform movements have not been described (15)(16)(17)(18)(19)(20). We therefore used a primate model of HD to evaluate whether striatal cell replacement in the degenerated striatum could ameliorate the characteristic motor symptoms observed. We also investigated whether such symptoms would reappear after removal of immunosuppressive treatment and if implanted nonstriatal neural precursor cells could have a beneficial effect. MATERIALS AND METHODSWe performed intrastriatal stereotaxic injections of IA into the right caudate-putamen complex of 15 baboons. Six weeks later, 5 of these animals received fetal rat striatal cells by injection into the lesioned caudate-putamen. In addition to these 5 transplanted animals a 6th baboon received a contro...

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“…In addition, the degree of spread ofreactive gliosis in the ipsilateral hemisphere was extensive; an effect not observed for the controls. (6, 7, 10), the early phase of the reactive gliosis process may actually be an attempt by astrocytes to promote recovery, given the many neurotrophic properties of this cell type that are increasingly being appreciated (41)(42)(43)(44). A means to resolve the role of astrocyte reactivity may come from the ability to diminish or enhance the gliotic process and to assess subsequent functional aspects.…”

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confidence: 99%

Gamma-interferon promotes proliferation of adult human astrocytes in vitro and reactive gliosis in the adult mouse brain in vivo.

Yong

Moumdjian

Yong

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

198

127

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Reactive gliosis is a characteristic response of astrocytes to inflammation and trauma of the central nervous system. To investigate whether soluble factors (cytokines) from inflammatory mononuclear cells that accumulate at lesion sites can provide the cellular signals to initiate gliosis and to identify such cytokines, we have tested and found that supernatants derived from subsets of activated human T lymphocytes (CD8' or CD41) are potent mitogens for cultured human adult astrocytes. This effect is blocked by a neutralizing antibody to -interferon (IFN). Recombinant A consideration in relating relevance of in vitro proliferation results to reactive gliosis in vivo is that gliotic scars seldom develop after insults to the embryonic brain (22-24) but are common features in adult brain injuries. Thus, it becomes important to assess proliferation of astrocytes derived from adult animals, rather than from neonatal ones. We have adopted such a strategy by using adult human astrocytes isolated from surgical brain biopsies and have addressed the following questions. Do activated human T lymphocytes produce sufficient cytokines to induce proliferation of cultured adult human astrocytes; if so, which cytokine (s) (see Results), were treated with trysin and seeded on poly(L-lysine)-coated (10 jag/ml) 9-mm Aclar fluorocarbon coverslips at 10,000 cells per coverslip. These mixed cells were used for the present study; methods for eliminating microglia from rodent glia cultures (leucine methyl ester and silica ingestion) (28-30) were not effective for human preparations. Culture medium was Eagle's minimum essential medium supplemented with 5% (vol/vol) fetal calf serum, Gentamicin (20 gg/ml), and dextrose (1 mg/ml) (all from GIBCO).

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Transplants of purified astrocytes promote behavioral recovery after frontal cortex ablation

Cited by 206 publications

References 11 publications

Astrogliosis in the Neonatal and Adult Murine Brain Post-Trauma: Elevation of Inflammatory Cytokines and the Lack of Requirement for Endogenous Interferon-γ

Astrogliosis in the Neonatal and Adult Murine Brain Post-Trauma: Elevation of Inflammatory Cytokines and the Lack of Requirement for Endogenous Interferon-γ

Intrastriatal transplantation of cross-species fetal striatal cells reduces abnormal movements in a primate model of Huntington disease.

Gamma-interferon promotes proliferation of adult human astrocytes in vitro and reactive gliosis in the adult mouse brain in vivo.

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