Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Retinal repair by transplantation of photoreceptor precursors

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Integration of P1 retinal cells into immature and adult wild-type recipient retinas.
Figure 2: Optimal ontogenetic stage of donor cells is the post-mitotic photoreceptor precursor.
Figure 3: Photoreceptor identity and synaptic connectivity of integrated cells.
Figure 4: Integration and restoration of light sensitivity in degenerating recipient retinas.

References

  1. Chacko, D. M., Rogers, J. A., Turner, J. E. & Ahmad, I. Survival and differentiation of cultured retinal progenitors transplanted in the subretinal space of the rat. Biochem. Biophys. Res. Commun. 268, 842–846 (2000)

    Article  CAS  PubMed  Google Scholar 

  2. Sakaguchi, D. S. et al. Transplantation of neural progenitor cells into the developing retina of the Brazilian opossum: an in vivo system for studying stem/progenitor cell plasticity. Dev. Neurosci. 26, 336–345 (2004)

    Article  CAS  PubMed  Google Scholar 

  3. Van Hoffelen, S. J., Young, M. J., Shatos, M. A. & Sakaguchi, D. S. Incorporation of murine brain progenitor cells into the developing mammalian retina. Invest. Ophthalmol. Vis. Sci. 44, 426–434 (2003)

    Article  PubMed  Google Scholar 

  4. Young, M. J., Ray, J., Whiteley, S. J., Klassen, H. & Gage, F. H. Neuronal differentiation and morphological integration of hippocampal progenitor cells transplanted to the retina of immature and mature dystrophic rats. Mol. Cell. Neurosci. 16, 197–205 (2000)

    Article  CAS  PubMed  Google Scholar 

  5. Young, R. W. Cell differentiation in the retina of the mouse. Anat. Rec. 212, 199–205 (1985)

    Article  CAS  PubMed  Google Scholar 

  6. Akimoto, M. et al. Targeting of green fluorescent protein to new-born rods by Nrl promoter and temporal expression profiling of flow-sorted photoreceptors. Proc. Natl Acad. Sci. USA 103, 3890–3895 (2006)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  7. Okabe, M., Ikawa, M., Kominami, K., Nakanishi, T. & Nishimune, Y. 'Green mice' as a source of ubiquitous green cells. FEBS Lett. 407, 313–319 (1997)

    Article  CAS  PubMed  Google Scholar 

  8. Yang, P., Seiler, M. J., Aramant, R. B. & Whittemore, S. R. Differential lineage restriction of rat retinal progenitor cells in vitro and in vivo. J. Neurosci. Res. 69, 466–476 (2002)

    Article  CAS  PubMed  Google Scholar 

  9. Carter-Dawson, L. D. & LaVail, M. M. Rods and cones in the mouse retina. II. Autoradiographic analysis of cell generation using tritiated thymidine. J. Comp. Neurol. 188, 263–272 (1979)

    Article  CAS  PubMed  Google Scholar 

  10. Terada, N. et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416, 542–545 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Ying, Q. L., Nichols, J., Evans, E. P. & Smith, A. G. Changing potency by spontaneous fusion. Nature 416, 545–548 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  12. Weimann, J. M., Johansson, C. B., Trejo, A. & Blau, H. M. Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nature Cell Biol. 5, 959–966 (2003)

    Article  CAS  PubMed  Google Scholar 

  13. Hadjantonakis, A. K., Macmaster, S. & Nagy, A. Embryonic stem cells and mice expressing different GFP variants for multiple non-invasive reporter usage within a single animal. BMC Biotechnol. 2, 11 (2002)

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kashofer, K. & Bonnet, D. Gene therapy progress and prospects: stem cell plasticity. Gene Ther. 12, 1229–1234 (2005)

    Article  CAS  PubMed  Google Scholar 

  15. Swaroop, A. et al. A conserved retina specific gene encodes a basic motif/leucine zipper domain. Proc. Natl Acad. Sci. USA 89, 266–270 (1992)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mears, A. J. et al. Nrl is required for rod photoreceptor development. Nature Genet. 29, 447–452 (2001)

    Article  CAS  PubMed  Google Scholar 

  17. Swain, P. K. et al. Multiple phosphorylated isoforms of NRL are expressed in rod photoreceptors. J. Biol. Chem. 276, 36824–36830 (2001)

    Article  CAS  PubMed  Google Scholar 

  18. tom Dieck, S. et al. Molecular dissection of the photoreceptor ribbon synapse: physical interaction of Bassoon and RIBEYE is essential for the assembly of the ribbon complex. J. Cell Biol. 168, 825–836 (2005)

    Article  PubMed  PubMed Central  Google Scholar 

  19. Koulen, P., Kuhn, R., Wassle, H. & Brandstatter, J. H. Modulation of the intracellular calcium concentration in photoreceptor terminals by a presynaptic metabotropic glutamate receptor. Proc. Natl Acad. Sci. USA 96, 9909–9914 (1999)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  20. Koulen, P. & Brandstatter, J. H. Pre- and postsynaptic sites of action of mGluR8a in the mammalian retina. Invest. Ophthalmol. Vis. Sci. 43, 1933–1940 (2002)

    PubMed  Google Scholar 

  21. Wells, J. et al. Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy. Nature Genet. 3, 213–218 (1993)

    Article  CAS  PubMed  Google Scholar 

  22. McLaughlin, M. E., Sandberg, M. A., Berson, E. L. & Dryja, T. P. Recessive mutations in the gene encoding the beta-subunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nature Genet. 4, 130–134 (1993)

    Article  CAS  PubMed  Google Scholar 

  23. Rosenfeld, P. J. et al. A null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa. Nature Genet. 1, 209–213 (1992)

    Article  CAS  PubMed  Google Scholar 

  24. Reuter, J. H. & Sanyal, S. Development and degeneration of retina in rds mutant mice: the electroretinogram. Neurosci. Lett. 48, 231–237 (1984)

    Article  CAS  PubMed  Google Scholar 

  25. Sanyal, S., Hawkins, R. K. & Zeilmaker, G. H. Development and degeneration of retina in rds mutant mice: analysis of interphotoreceptor matrix staining in chimaeric retina. Curr. Eye Res. 7, 1183–1190 (1988)

    Article  CAS  PubMed  Google Scholar 

  26. Carter-Dawson, L. D., LaVail, M. M. & Sidman, R. L. Differential effect of the rd mutation on rods and cones in the mouse retina. Invest. Ophthalmol. Vis. Sci. 17, 489–498 (1978)

    CAS  PubMed  Google Scholar 

  27. Humphries, M. M. et al. Retinopathy induced in mice by targeted disruption of the rhodopsin gene. Nature Genet. 15, 216–219 (1997)

    Article  CAS  PubMed  Google Scholar 

  28. Toda, K., Bush, R. A., Humphries, P. & Sieving, P. A. The electroretinogram of the rhodopsin knockout mouse. Vis. Neurosci. 16, 391–398 (1999)

    Article  CAS  PubMed  Google Scholar 

  29. Lucas, R. J., Douglas, R. H. & Foster, R. G. Characterization of an ocular photopigment capable of driving pupillary constriction in mice. Nature Neurosci. 4, 621–626 (2001)

    Article  CAS  PubMed  Google Scholar 

Download references

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

Authors and Affiliations

Authors

Corresponding author

Correspondence to R. R. Ali.

Ethics declarations

Competing interests

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

Supplementary information

Supplementary Methods

This file contains additional details of the methods used in this study. (DOC 56 kb)

Supplementary Figure Legends

Text to accompany the below Supplementary Figures. (DOC 25 kb)

Supplementary Figure 1

Schematic summary of findings (JPG 117 kb)

Supplementary Figure 2

Transplantation occurs via integration not cell fusion. (JPG 42 kb)

Supplementary Figure 3

E11.5 cells express markers of progenitor cells. (JPG 49 kb)

Supplementary Figure 4

E11.5 cells survive and are able to differentiate in the subretinal space of adult host retinas. (JPG 87 kb)

Supplementary Figure 5

Transplantation into the rd mouse. (JPG 34 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

MacLaren, R., Pearson, R., MacNeil, A. et al. Retinal repair by transplantation of photoreceptor precursors. Nature 444, 203–207 (2006). https://doi.org/10.1038/nature05161

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05161

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing