Human Müller stem cell (MIO-M1) transplantation in a rat model of glaucoma: survival, differentiation, and integration.
OBJECTIVE
Stem cell transplantation is a potential treatment strategy for neurodegenerative diseases such as glaucoma. The Müller stem cell line MIO-M1 can be differentiated to produce retinal neurons and glia. The survival, migration, differentiation, and integration of MIO-M1 cells were investigated in a rat model of glaucoma. The effect of modulating the retinal environment with either chondroitinase ABC or erythropoietin was also studied.


METHODS
Intraocular pressure was chronically increased unilaterally 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 immune 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 markers such as PSA-NCAM, GFAP, and beta-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.
Bull
Natalie D
ND
Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.
Limb
G Astrid
GA
Martin
Keith R
KR
D053687:Adult Stem Cells / Q000637:transplantation*; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D019765:Chondroitin ABC Lyase / Q000494:pharmacology; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000494:pharmacology; D019084:Fluorescent Antibody Technique, Indirect; D005901:Glaucoma / Q000601:surgery*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006085:Graft Survival / Q000502:physiology*; D049452:Green Fluorescent Proteins; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007429:Intraocular Pressure; D008297:Male; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism / Q000637:transplantation*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D012160:Retina / Q000166:cytology / Q000187:drug effects; D012794:Sialic Acids / Q000378:metabolism; D033581:Stem Cell Transplantation; D014162:Transfection; D014404:Tubulin / Q000378:metabolism
D005904:Glial Fibrillary Acidic Protein; D007166:Immunosuppressive Agents; D039842:Neural Cell Adhesion Molecule L1; D011994:Recombinant Proteins; D012794:Sialic Acids; C498585:TUBB3 protein, human; D014404:Tubulin; C485184:enhanced green fluorescent protein; C103469:polysialyl neural cell adhesion molecule; D004921:Erythropoietin; D049452:Green Fluorescent Proteins; D019765:Chondroitin ABC Lyase