1Department of Genetics, Institute of Opthalmology, London, United Kingdom
2Nuffield Laboratory of Opthalmology, University of Oxford, Oxford, United Kingdom
3Developmental Biology Unit, UCL Institute of Child Health, London, United Kingdom
Commercial Relationships: A.C. Barber, None; R.E. MacLaren, None; J.W.B. Bainbridge, None; J. Sowden, None; R.R. Ali, None; R.A. Pearson, None.
Support: The Wellcome Trust, NIHR Biomedical Research Centre for Ophthalmology
Purpose:Cell transplantation can successfully restore the pupillary reflex in animal models of retinal degeneration. However, greater numbers of integrated cells are required to restore visual function in humans. The host retinal environment may play affect transplanted donor cell migration and integration. Retinal degeneration is often associated with reactive gliosis, a process characterized by up-regulation of intermediate filament proteins, Muller cell proliferation and gliotic scar formation in the subretinal space. The aim of this study is to characterize the progression of gliosis in animal models of retinal degeneration and examine whether this impacts on the integration of transplanted photoreceptor precursors.
Methods:Eyes from Rho-/- and Crb1rd8/rd8 mice were taken at various time points between 2 and 12 weeks of age. Gliosis was characterized by immunohistochemistry using antibodies against GFAP, Vimentin, chondroitin sulphate and glutamate synthase. To investigate the potential impact of gliosis on cell integration, early post-natal photoreceptor precursors were transplanted into recipient animals via subretinal injection. Three weeks post injection integrated photoreceptor cells in the ONL were counted.
Results:Immunohistochemistry showed an up-regulation of GFAP and Vimentin in both animal models. Gliotic scars were observed extending into the subretinal space. The number of integrated photoreceptors was inversely correlated with the extent of gliosis; markers of gliosis increased with age and advancing degeneration while the number of integrated cells decreased. In the older recipients, transplanted cells were frequently observed on top of the glial scar with processes extending laterally along the surface on the neural retina. The number of integrated photoreceptors in wildtype animals remained constant across the same age range.
Conclusions:This data suggests that reactive gliosis and the subsequent gliotic scars present a significant barrier to cell integration in animal models of retinal degeneration. Preventing formation or breaking down of the gliotic scar may prove to be a useful strategy to enhance photoreceptor integration.
Keywords: transplantation photoreceptors Muller cells
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