Letter | Published:

Retinal repair by transplantation of photoreceptor precursors

Nature volume 444, pages 203207 (09 November 2006) | Download Citation

Subjects

Abstract

Photoreceptor loss causes irreversible blindness in many retinal diseases. Repair of such damage by cell transplantation is one of the most feasible types of central nervous system repair; photoreceptor degeneration initially leaves the inner retinal circuitry intact and new photoreceptors need only make single, short synaptic connections to contribute to the retinotopic map. So far, brain- and retina-derived stem cells transplanted into adult retina have shown little evidence of being able to integrate into the outer nuclear layer and differentiate into new photoreceptors1,2,3,4. Furthermore, there has been no demonstration that transplanted cells form functional synaptic connections with other neurons in the recipient retina or restore visual function. This might be because the mature mammalian retina lacks the ability to accept and incorporate stem cells or to promote photoreceptor differentiation. We hypothesized that committed progenitor or precursor cells at later ontogenetic stages might have a higher probability of success upon transplantation. Here we show that donor cells can integrate into the adult or degenerating retina if they are taken from the developing retina at a time coincident with the peak of rod genesis5. These transplanted cells integrate, differentiate into rod photoreceptors, form synaptic connections and improve visual function. Furthermore, we use genetically tagged post-mitotic rod precursors expressing the transcription factor Nrl (ref. 6) (neural retina leucine zipper) to show that successfully integrated rod photoreceptors are derived only from immature post-mitotic rod precursors and not from proliferating progenitor or stem cells. These findings define the ontogenetic stage of donor cells for successful rod photoreceptor transplantation.

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Acknowledgements

We thank Y. Duran and N. Gent for technical assistance, P. Humphries for providing the rhodopsin knockout mouse, R. Molday and G. Travis for providing antibodies, and J. Partridge for light calibrations. This work was supported by grants from the Medical Research Council UK, the Royal Blind Asylum and School and The Scottish National Institute for the War Blinded. Development of the Nrl-gfp+/+ transgenic line was supported by grants from the National Institutes of Health, The Foundation Fighting Blindness and Research to Prevent Blindness.

Author information

Author notes

    • R. E. MacLaren
    •  & R. A. Pearson

    These authors contributed equally to this work.

    • M. Akimoto

    Present address: Translational Research Center, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan.

Affiliations

  1. Division of Molecular Therapy, University College London Institute of Ophthalmology, 11–43 Bath Street, London EC1V 9EL, UK

    • R. E. MacLaren
    • , A. MacNeil
    •  & R. R. Ali
  2. Vitreoretinal Service, Moorfields Eye Hospital, 162 City Road, London EC1V 2PD, UK

    • R. E. MacLaren
  3. Developmental Biology Unit, University College London Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK

    • R. A. Pearson
    •  & J. C. Sowden
  4. Henry Wellcome Laboratory for Vision Sciences, Department of Optometry and Visual Science, City University, Northampton Square, London EC1V 0HB, UK

    • R. H. Douglas
  5. Division of Visual Science, University College London Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK

    • T. E. Salt
  6. Department of Ophthalmology and Visual Sciences and,

    • M. Akimoto
    •  & A. Swaroop
  7. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48105, USA

    • A. Swaroop
  8. Molecular Immunology Unit, University College London Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK

    • R. R. Ali

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Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding author

Correspondence to R. R. Ali.

Supplementary information

Word documents

  1. 1.

    Supplementary Methods

    This file contains additional details of the methods used in this study.

  2. 2.

    Supplementary Figure Legends

    Text to accompany the below Supplementary Figures.

Image files

  1. 1.

    Supplementary Figure 1

    Schematic summary of findings

  2. 2.

    Supplementary Figure 2

    Transplantation occurs via integration not cell fusion.

  3. 3.

    Supplementary Figure 3

    E11.5 cells express markers of progenitor cells.

  4. 4.

    Supplementary Figure 4

    E11.5 cells survive and are able to differentiate in the subretinal space of adult host retinas.

  5. 5.

    Supplementary Figure 5

    Transplantation into the rd mouse.

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DOI

https://doi.org/10.1038/nature05161

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