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Restoration of vision after transplantation of photoreceptors

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Abstract

Cell transplantation is a potential strategy for treating blindness caused by the loss of photoreceptors. Although transplanted rod-precursor cells are able to migrate into the adult retina and differentiate to acquire the specialized morphological features of mature photoreceptor cells1, the fundamental question remains whether transplantation of photoreceptor cells can actually improve vision. Here we provide evidence of functional rod-mediated vision after photoreceptor transplantation in adult Gnat1−/− mice, which lack rod function and are a model of congenital stationary night blindness2. We show that transplanted rod precursors form classic triad synaptic connections with second-order bipolar and horizontal cells in the recipient retina. The newly integrated photoreceptor cells are light-responsive with dim-flash kinetics similar to adult wild-type photoreceptors. By using intrinsic imaging under scotopic conditions we demonstrate that visual signals generated by transplanted rods are projected to higher visual areas, including V1. Moreover, these cells are capable of driving optokinetic head tracking and visually guided behaviour in the Gnat1−/− mouse under scotopic conditions. Together, these results demonstrate the feasibility of photoreceptor transplantation as a therapeutic strategy for restoring vision after retinal degeneration.

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Figure 1: Improved transplantation protocols significantly improve photoreceptor integration into the adult Gnat1 −/− model of retinal dysfunction.
Figure 2: Transplanted Nrl-GFP + rod photoreceptors are light-responsive and project light information to the visual cortex.
Figure 3: Rescue of scotopic optokinetic head-tracking behaviour in Nrl-GFP -treated Gnat1 −/− mice.
Figure 4: Nrl-GFP -treated Gnat1 −/− mice can solve the visually guided water-maze task under scotopic conditions.

Change history

  • 25 April 2012

    The original supplementary information PDF contained an error in Supplementary Figure 3. This has now been corrected and the file replaced.

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Acknowledgements

This work was supported by the Medical Research Council UK (G03000341), the Wellcome Trust (082217), the Royal Society (RG080398), the British Retinitis Pigmentosa Society (GR566) and The Miller’s Trust. R.A.P. is a Royal Society University Research Fellow. R.R.A is partly funded by the Department of Health’s National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and Alcon Research Institute. J.C.S. is supported by Great Ormond Street Hospital Children’s Charity. T.X. and K.-W.Y. were supported by a US National Institutes of Health grant (EY06837) and the António Champalimaud Vision Award (Portugal). C.H.S. was supported by grants EY11307, EY016805, Research to Prevent Blindness. M.C. holds the GlaxoSmithKline/Fight for Sight Chair in Visual Neuroscience and is supported by the European Research Council. We thank Y. Umino and the late R. Barlow for advice and training with optomotor recordings, A. Eddaoudi for FACS assistance, G. Holder for advice on ERG recordings, C. Hogg for light calibrations, L. Cao for technical suggestions on suction-pipette recordings, and the Department of Genetics, UCL Institute of Ophthalmology, for discussions on the data.

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Authors and Affiliations

Authors

Contributions

R.A.P. contributed to the concept, design, execution and analysis of all experiments, funding, and wrote the manuscript. A.C.B. contributed to the design, execution and analysis of experiments except single-cell recordings, electron microscopy and behavioural assessments. M.R., A.B. and M.C. contributed to the design, execution and analysis of the intrinsic optical-imaging experiments. C.H., A.J.S. and S.A.A. contributed to the design and execution of the AAV gene supplementation studies, and C.H. the execution of the water-maze tests. Y.D. contributed to the histological processing and execution of the water-maze tests. J.W.B., E.L.W. and U.F.O.L. contributed to the optimization of transplantation protocols. T.X. performed the single-cell recordings. K.W.Y. contributed to the design and analysis of the single-cell recordings. C.H.S. and J.Z.C. performed the ultrastructural analysis. J.C.S. and R.R.A. contributed to the concept and design of the experiments, funding and to manuscript writing.

Corresponding authors

Correspondence to R. A. Pearson or R. R. Ali.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures and Legends 1–5, Supplementary Methods, the legend for Movie 1 and additional references. The original file posted online contained an error in Supplementary Figure 3. This has now been corrected and the file replaced on 25 April 2012. (PDF 2077 kb)

Supplementary Movie 1

This movie shows examples of swimming behaviour in non-injected C57BL/6 wildtype and Gnat1-/- controls, Gnat1-/- mice receiving Gnat1-/- cell (sham) injections and Gnat1-/- mice receiving Nrl.GFP+ve-rod-precursors, tested under scotopic conditions) see Supplementary Informaiton file for full legend. (MOV 30537 kb)

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Pearson, R., Barber, A., Rizzi, M. et al. Restoration of vision after transplantation of photoreceptors. Nature 485, 99–103 (2012). https://doi.org/10.1038/nature10997

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