title: Allogeneic Transplantation of Müller-Derived Retinal Ganglion Cells Improves Retinal Function in a Feline Model of Ganglion Cell Depletion.
abstract: Human Müller glia with stem cell characteristics (hMGSCs) have been shown to improve retinal function upon transplantation into rat models of retinal ganglion cell (RGC) depletion. However, their translational potential may depend upon successful engraftment and improvement of retinal function in experimental models with anatomical and functional features resembling those of the human eye. We investigated the effect of allogeneic transplantation of feline Müller glia with the ability to differentiate into cells expressing RGC markers, following ablation of RGCs by N-methyl-d-aspartate (NMDA). Unlike previous observations in the rat, transplantation of hMGSC-derived RGCs into the feline vitreous formed aggregates and elicited a severe inflammatory response without improving visual function. In contrast, allogeneic transplantation of feline MGSC (fMGSC)-derived RGCs into the vitrectomized eye improved the scotopic threshold response (STR) of the electroretinogram (ERG). Despite causing functional improvement, the cells did not attach onto the retina and formed aggregates on peripheral vitreous remnants, suggesting that vitreous may constitute a barrier for cell attachment onto the retina. This was confirmed by observations that cellular scaffolds of compressed collagen and enriched preparations of fMGSC-derived RGCs facilitated cell attachment. Although cells did not migrate into the RGC layer or the optic nerve, they significantly improved the STR and the photopic negative response of the ERG, indicative of increased RGC function. These results suggest that MGSCs have a neuroprotective ability that promotes partial recovery of impaired RGC function and indicate that cell attachment onto the retina may be necessary for transplanted cells to confer neuroprotection to the retina. Significance: Müller glia with stem cell characteristics are present in the adult human retina, but they do not have regenerative ability. These cells, however, have potential for development of cell therapies to treat retinal disease. Using a feline model of retinal ganglion cell (RGC) depletion, cell grafting methods to improve RGC function have been developed. Using cellular scaffolds, allogeneic transplantation of Müller glia-derived RGC promoted cell attachment onto the retina and enhanced retinal function, as judged by improvement of the photopic negative and scotopic threshold responses of the electroretinogram. The results suggest that the improvement of RGC function observed may be ascribed to the neuroprotective ability of these cells and indicate that attachment of the transplanted cells onto the retina is required to promote effective neuroprotection.
authors.affiliation: Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Silke
authors.initials: S
authors.lastname: Becker
authors.affiliation: Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Eastlake
authors.affiliation: National Institute for Health Research Biomedical Research Centre for Ophthalmology, Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Hari
authors.initials: H
authors.lastname: Jayaram
authors.affiliation: Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Megan F
authors.initials: MF
authors.lastname: Jones
authors.affiliation: Institute of Orthopaedics and Musculoskeletal Science, University College London, London, United Kingdom.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Brown
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Gillian J
authors.initials: GJ
authors.lastname: McLellan
authors.affiliation: National Institute for Health Research Biomedical Research Centre for Ophthalmology, Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: David G
authors.initials: DG
authors.lastname: Charteris
authors.affiliation: National Institute for Health Research Biomedical Research Centre for Ophthalmology, Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Peng T
authors.initials: PT
authors.lastname: Khaw
authors.affiliation: National Institute for Health Research Biomedical Research Centre for Ophthalmology, Institute of Ophthalmology, University College London, London, United Kingdom g.limb@ucl.ac.uk.
authors.forename: G Astrid
authors.initials: GA
authors.lastname: Limb
mesh_terms: D000818:Animals; D002415:Cats; D002448:Cell Adhesion; D003094:Collagen / Q000737:chemistry; D004195:Disease Models, Animal; D004596:Electroretinography; D063928:Ependymoglial Cells / Q000166:cytology / Q000502:physiology / Q000637:transplantation*; D006801:Humans; D016202:N-Methylaspartate; D000066829:Neuroprotection; D061251:Primary Cell Culture; D012162:Retinal Degeneration / Q000139:chemically induced / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000502:physiology / Q000637:transplantation*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D054457:Tissue Scaffolds; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous; D014821:Vitrectomy; D014822:Vitreous Body / Q000601:surgery
chemical_list: D016202:N-Methylaspartate; D003094:Collagen
keywords: Müller cells; Retinal degeneration; Retinal ganglion cells; Stem cells