Transplantation of reprogrammed embryonic stem cells improves visual function in a mouse model for retinitis pigmentosa.
BACKGROUND
To study whether C57BL/6J-Tyr/J (C2J) mouse embryonic stem (ES) cells can differentiate into retinal pigment epithelial (RPE) cells in vitro and then restore retinal function in a model for retinitis pigmentosa: Rpe65/Rpe65 C57BL6 mice.


METHODS
Yellow fluorescent protein (YFP)-labeled C2J ES cells were induced to differentiate into RPE-like structures on PA6 feeders. RPE-specific markers are expressed from differentiated cells in vitro. After differentiation, ES cell-derived RPE-like cells were transplanted into the subretinal space of postnatal day 5 Rpe65/Rpe65 mice. Live imaging of YFP-labeled C2J ES cells demonstrated survival of the graft. Electroretinograms (ERGs) were performed on transplanted mice to evaluate the functional outcome of transplantation.


RESULTS
RPE-like cells derived from ES cells sequentially express multiple RPE-specific markers. After transplantation, YFP-labeled cells can be tracked with live imaging for as long as 7 months. Although more than half of the mice were complicated with retinal detachments or tumor development, one fourth of the mice showed increased electroretinogram responses in the transplanted eyes. Rpe65/Rpe65 mice transplanted with RPE-like cells showed significant visual recovery during a 7-month period, whereas those injected with saline, PA6 feeders, or undifferentiated ES cells showed no rescue.


CONCLUSIONS
ES cells can differentiate, morphologically, and functionally, into RPE-like cells. Based on these findings, differentiated ES cells have the potential for the development of new therapeutic approaches for RPE-specific diseases such as certain forms of retinitis pigmentosa and macular degeneration. Nevertheless, stringent control of retinal detachment and teratoma development will be necessary before initiation of treatment trials.
Wang
Nan-Kai
NK
Department of Ophthalmology, Columbia University, New York City, NY, USA.
Tosi
Joaquin
J
Kasanuki
Jennifer Mie
JM
Chou
Chai Lin
CL
Kong
Jian
J
Parmalee
Nancy
N
Wert
Katherine J
KJ
Allikmets
Rando
R
Lai
Chi-Chun
CC
Chien
Chung-Liang
CL
Nagasaki
Takayuki
T
Lin
Chyuan-Sheng
CS
Tsang
Stephen H
SH
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D048430:Cell Shape; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004596:Electroretinography; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000637:transplantation*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009154:Mutation; D020127:Recovery of Function; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D013997:Time Factors; D014162:Transfection; D014785:Vision, Ocular; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
D015415:Biomarkers; D002352:Carrier Proteins; D005136:Eye Proteins; D008164:Luminescent Proteins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase