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N. D. Bull, G. A. Limb, K. R. Martin; Intraocular Transplantation of Adult Human Muller Progenitor Cells (MIO-M1) in a Rat Glaucoma Model. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4376.
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Transplantation of neural stem/progenitor cells offers a potential treatment strategy for neurodegenerative diseases such as glaucoma. The MIO-M1 cell line, isolated from post-mortem adult human retina, can be differentiated in vitro to produce cells expressing markers of mature retinal neurons and glia. We investigated the survival, migration, differentiation and integration of MIO-M1 derived cells in a rat model of glaucoma.
MIO-M1 cells were transfected to express GFP and expanded in vitro. Unilateral experimental glaucoma was induced in adult rats by laser treatment to the trabecular meshwork to increase intraocular pressure chronically (n=28). 21 days following glaucoma induction, MIO-M1 derived cells were transplanted into the vitreous of glaucomatous eyes and one eye of non-glaucoma controls (n=6). Oral immunosuppressants (prednisolone, azathioprine and cyclosporin A) were administered to reduce xenograft rejection. Survival, migration, differentiation and integration of grafted cells were assessed at 1, 2 and 4 weeks by immunohistochemistry.
Without immune suppression, transplanted cells were eliminated within days. Immunosuppression facilitated survival of transplanted cells for at least 2 weeks in glaucoma and control eyes. Despite immunosuppression, macrophage infiltration and a dramatic reduction in graft survival was seen at later timepoints. Grafted cells displayed a migratory phenotype with an elongated bipolar shape and both leading and trailing processes. Cells did not express PSA-NCAM, characteristic of migrating neuroblasts in other parts of the CNS. Exposure of the progenitor cells to bFGF plus basement membrane protein prior to transplantation did not enhance their ability to migrate into the retina. Many transplanted cells expressed the early neuronal marker ßIII-tubulin or the glial marker GFAP. However, transplanted cells failed to integrate into the retina.
MIO-M1 cells isolated from the adult human retina survived for at least 2 weeks in glaucoma and control eyes of immunosuppressed rats, displayed a migratory phenotype and expressed neuronal and glial markers. The results suggest that macrophage reactivity may contribute to the lack of cell integration. Further studies are underway to promote retinal integration by modifying the inhibitory environment and to test syngeneic transplantation.
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