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G. A. Limb, S. Singhal, J. M. Lawrence, B. Bhatia, J. S. Ellis, A. S. Kwan, M. T. Perez, P. J. Luthert, J. W. Fawcett, P. T. Khaw; Microglia and Chondroitin Sulphate Proteoglycans Prevent the Migration and Integration of Retinal Stem Cells Into Degenerated Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2037. doi: https://doi.org/.
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At present there are major limitations to successful migration and integration of retinal stem cells when grafted into degenerated retina to restore visual function. This study investigated the role of chondroitin sulphate proteoglycans (CSPGs) and microglia on the migration and integration of human Müller stem cells after subretinal injection into animal models of retinal degeneration.
Müller stem cells were transplanted into the subretinal space of neonate Lister Hooded and Royal College of Surgeons (RCS) rats in the presence or absence of chondroitinase ABC. Animals underwent oral immunosuppression and anti-inflammatory therapy combined with intraperitoneal indomethacine for the duration of the experiments. Müller cell migration and microglial infiltration, as well as CSPG expression were assessed immunohistologically.
Neonate LH rat retina showed minimal microglial accumulation (CD68+ cells) which increased significantly after transplantation (p<0.001). In contrast, 5 week old RCS rat retina showed severe microglial accumulation in the outer nuclear layer (ONL) and photoreceptor outer segment debris zone (DZ) which further increased (p< 0.05) after transplantation. Marked deposition of the N-terminal fragment of CSPGs, as well as neurocan and versican was observed in the DZ of 5 week old RCS rat retinae. This contrasted with the limited expression of these proteins in the GCL of the adult and neonate LH rat retinae. CSPGs and CD68+ cells co-localized within the ONL and DZ of degenerating RCS rat retina. Enhanced anti-inflammatory therapy markedly decreased microglia accumulation, but did not facilitate Müller stem cell migration. However, injection of cells with Chondroitinase ABC (ChABC) combined with enhanced anti-inflammatory treatment dramatically increased migration of grafted cells into the retina.
These observations suggest that both microglia and CSPGs constitute a barrier for stem cell migration into degenerated retina. They also indicate that control of matrix deposition and innate microglial response to neural degeneration needs to be addressed when translating cell based therapies to treat human retinal disease.
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