Photoreceptor precursors derived from three-dimensional embryonic stem cell cultures integrate and mature within adult degenerate retina

• Published in: Nature biotechnology Vol. 31; no. 8; pp. 741 - 747
• Main Authors: Gonzalez-Cordero, Anai, West, Emma L, Pearson, Rachael A, Duran, Yanai, Carvalho, Livia S, Chu, Colin J, Naeem, Arifa, Blackford, Samuel J I, Georgiadis, Anastasios, Lakowski, Jorn, Hubank, Mike, Smith, Alexander J, Bainbridge, James W B, Sowden, Jane C, Ali, Robin R
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2013; Nature Publishing Group
• Subjects: 631/532/1360; Agriculture; Animals; Bioinformatics; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Blindness - genetics; Blindness - pathology; Blindness - therapy; Cell culture; Cell Culture Techniques; Cell Differentiation; Cell- and Tissue-Based Therapy; Developmental stages; Embryonic Stem Cells - cytology; Embryonic Stem Cells - transplantation; Embryos; Green Fluorescent Proteins; letter; Life Sciences; Mice; Neurons; Photoreception; Photoreceptor Cells; Photoreceptor Cells, Vertebrate; Photoreceptors; Physiological aspects; Retina; Retina - cytology; Retina - metabolism; Retina - pathology; Rhodopsin - genetics; Rhodopsin - metabolism; Stem Cell Transplantation; Stem cells; Transplantation
• ISSN: 1087-0156; 1546-1696; 1546-1696
• DOI: 10.1038/nbt.2643

Optic cup-like structures generated from mouse ES cells produce photoreceptor precursors that integrate and mature in vivo in three models of retinal degeneration. Irreversible blindness caused by loss of photoreceptors may be amenable to cell therapy. We previously demonstrated retinal repair 1 and restoration of vision through transplantation of photoreceptor precursors obtained from postnatal retinas into visually impaired adult mice 2 , 3 . Considerable progress has been made in differentiating embryonic stem cells (ESCs) in vitro toward photoreceptor lineages 4 , 5 , 6 . However, the capability of ESC-derived photoreceptors to integrate after transplantation has not been demonstrated unequivocally. Here, to isolate photoreceptor precursors fit for transplantation, we adapted a recently reported three-dimensional (3D) differentiation protocol that generates neuroretina from mouse ESCs 6 . We show that rod precursors derived by this protocol and selected via a GFP reporter under the control of a Rhodopsin promoter integrate within degenerate retinas of adult mice and mature into outer segment–bearing photoreceptors. Notably, ESC-derived precursors at a developmental stage similar to postnatal days 4–8 integrate more efficiently compared with cells at other stages. This study shows conclusively that ESCs can provide a source of photoreceptors for retinal cell transplantation.