Transplantation of photoreceptors derived from human Muller glia restore rod function in the P23H rat.
Müller glia possess stem cell characteristics that have been recognized to be responsible for the regeneration of injured retina in fish and amphibians. Although these cells are present in the adult human eye, they are not known to regenerate human retina in vivo. Human Müller glia with stem cell characteristics (hMSCs) can acquire phenotypic and genotypic characteristics of rod photoreceptors in vitro, suggesting that they may have potential for use in transplantation strategies to treat human photoreceptor degenerations. Much work has been undertaken in rodents using various sources of allogeneic stem cells to restore photoreceptor function, but the effect of human Müller glia-derived photoreceptors in the restoration of rod photoreceptor function has not been investigated. This study aimed to differentiate hMSCs into photoreceptor cells by stimulation with growth and differentiation factors in vitro to upregulate gene and protein expression of CRX, NR2E3, and rhodopsin and various phototransduction markers associated with rod photoreceptor development and function and to examine the effect of subretinal transplantation of these cells into the P23H rat, a model of primary photoreceptor degeneration. Following transplantation, hMSC-derived photoreceptor cells migrated and integrated into the outer nuclear layer of the degenerated retinas and led to significant improvement in rod photoreceptor function as shown by an increase in a-wave amplitude and slope using scotopic flash electroretinography. These observations suggest that hMSCs can be regarded as a cell source for development of cell-replacement therapies to treat human photoreceptor degenerations and may also offer potential for the development of autologous transplantation.
Ocular Biology & Therapeutics, UCL Institute of Ophthalmology, London, United Kingdom; NIHR Biomedical Research Centre for Ophthalmology, UCL Institute of Ophthalmology & Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom.
Hari
H
Jayaram
Megan F
MF
Jones
Karen
K
Eastlake
Phillippa B
PB
Cottrill
Silke
S
Becker
Joseph
J
Wiseman
Peng T
PT
Khaw
G Astrid
GA
Limb
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D004195:Disease Models, Animal; D004596:Electroretinography; D063928:Ependymoglial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020127:Recovery of Function; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D014785:Vision, Ocular
D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C403073:NR2E3 protein, human; D057093:Orphan Nuclear Receptors; D015534:Trans-Activators; C109288:cone rod homeobox protein; D012243:Rhodopsin
Müller glia; Photoreceptors; Repair and regeneration; Retina; Stem cells; Transplantation