Human Müller Stem Cell (MIO-M1) Transplantation in a Rat Model of Glaucoma: Survival, Differentiation, and Integration

PURPOSE. Stem cell transplantation is a potential treatment strat- egy for neurodegenerative diseases such as glaucoma. The Muller stem cell line MIO-M1 can be differentiated to produce retinal neurons and glia. The survival, migration, differentia- tion, and integration of MIO-M1 cells were investigated in a rat model of glaucoma. The effect of modulating the retinal envi- ronment with either chondroitinase ABC or erythropoietin was also studied. METHODS. Intraocular pressure was chronically increased uni- laterally by using a laser glaucoma model in adult rats. EGFP- transduced MIO-M1 cells were transplanted into the vitreous or subretinal space of glaucomatous or untreated eyes. Oral im- mune suppressants were administered to reduce xenograft rejection. Survival, migration, differentiation, and integration of grafted cells were assessed by immunohistochemistry. RESULTS. Transplanted cells survived for 2 to 3 weeks in vivo, although microglia/macrophage infiltration and a reduction in graft survival were seen by 4 weeks. Grafted cells displayed a migratory phenotype with an elongated bipolar shape often oriented toward the retina. Transplanted cells expressed mark- ers such as PSA-NCAM, GFAP, and -III-tubulin. The host retina was resistant to MIO-M1 migration, but modification of the local environment with erythropoietin or chondroitinase ABC facilitated retinal infiltration by MIO-M1 cells. CONCLUSIONS. The results demonstrate that differentiating MIO-M1 cells within the glaucomatous eye produced cells that expressed neuronal and glial cell markers. The retina was relatively resistant to transplant integration, and long-term xenograft survival was limited. However, local modulation of the retinal environment enhanced the integration of MIO-M1 cells into the glaucomatous retina. (Invest Ophthalmol Vis Sci. 2008;49:3449 -3456) DOI:10.1167/iovs.08-1770