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M. Takeda, D.F. Chen; Treatment of gliotoxin leads to robust integration into the adult retina from neural transplants . Invest. Ophthalmol. Vis. Sci. 2004;45(13):5179.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Success of retinal transplantation has been limited by restricted ability of neural implants to survive and integrate into the host. We hypothesize that retinal glial cells constitute a barrier demarcating the mature host retina from transplanted cells. To test this hypothesis, we examined efficiency of a gliotoxin – alpha amino–adipic acid (AAA), the glutamate analogue that selectively kills Muller glial cells and astrocytes – on neural integration after transplantation. Methods: To determine the effects of AAA on retinal cells, gliotoxin was injected into the subretinal space of adult wild–type mice or mice expressing enhanced green fluorescent protein driven under the promoter of glial fibrillary acidic protein (GFAP–GFP). Morphology and functions of retinal neuron and glial cells were examined. For transplantation studies, dissociated retinal cells isolated from neonatal (P0–2) mice overexpressing EGFP driven by a chicken beta–actin promoter and cytomegalovirus enhancer were injected into the subretinal space of adult wild–type mice. Host retinas were treated with AAA (0.5 mg/ml) or Saline at 2 days before transplantation by subretinal injection. Retinal flat–mounts were prepared at 21 days after transplantation, and numbers of EGFP cells survived and extended neuritis were counted. The lengths of neurites and the distances of cell spreading from the injection sites were measured. Results: Immediately after AAA injection, expression of GFAP was down–regulated around the injection site of the host retina, but it recovered after 5 days. Transplanted cells integrated robustly and extended longer neurites into the adult retina pre–treated with AAA compared with those treated with Saline. Conclusions: Our results demonstrate that retinal glial environment plays a crucial role in neural integration and neurite elongation after transplantation. Manipulating glial cell property with gliotoxin, AAA, may be a potential treatment that promotes the success of neural transplantation/replacement therapy.
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