May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Over-Expression of Developmentally Regulated Neurotrophins in the Adult Mouse Retina to Facilitate Integration of Transplanted Photoreceptor Precursor Cells
Author Affiliations & Notes
  • E. L. West
    Division of Molecular Therapy, Institute of Ophthalmology, UCL, London, United Kingdom
  • R. A. Pearson
    Division of Molecular Therapy, Institute of Ophthalmology, UCL, London, United Kingdom
  • Y. Duran
    Division of Molecular Therapy, Institute of Ophthalmology, UCL, London, United Kingdom
  • U. F. O. Luhmann
    Division of Molecular Therapy, Institute of Ophthalmology, UCL, London, United Kingdom
  • S. E. Barker
    Division of Molecular Therapy, Institute of Ophthalmology, UCL, London, United Kingdom
  • A. J. Smith
    Division of Molecular Therapy, Institute of Ophthalmology, UCL, London, United Kingdom
  • J. C. Sowden
    Developmental Biology Unit, Institute of Child Health, UCL, London, United Kingdom
  • R. E. MacLaren
    Division of Molecular Therapy, UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, United Kingdom
    NIHR Faculty, UCL/MEH London, United Kingdom
  • R. R. Ali
    Division of Molecular Therapy, Institute of Ophthalmology, UCL, London, United Kingdom
    NIHR Faculty, UCL/MEH London, United Kingdom
  • Footnotes
    Commercial Relationships  E.L. West, None; R.A. Pearson, None; Y. Duran, None; U.F.O. Luhmann, None; S.E. Barker, None; A.J. Smith, None; J.C. Sowden, None; R.E. MacLaren, None; R.R. Ali, None.
  • Footnotes
    Support  Medical Research Council UK, Fighting Blindess, Ireland, Royal Society UK, The Health Foundation UK
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 4279. doi:
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      E. L. West, R. A. Pearson, Y. Duran, U. F. O. Luhmann, S. E. Barker, A. J. Smith, J. C. Sowden, R. E. MacLaren, R. R. Ali; Over-Expression of Developmentally Regulated Neurotrophins in the Adult Mouse Retina to Facilitate Integration of Transplanted Photoreceptor Precursor Cells. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4279.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Photoreceptor cell transplantation provides a novel therapeutic strategy to repair the degenerate retina, although greater numbers are required than has been achieved thus far. Growth factors, such as CNTF, bFGF and IGF-1, provide important, tightly regulated signals that direct the proliferation and differentiation of progenitors in the CNS, including the retina, and play a role in regulating neural precursor cell migration. Neurotrophins may also influence the integration of transplanted photoreceptor precursors. It is therefore important to see whether modulating neurotrophin levels leads to a greater yield of integrated photoreceptors.

Methods: : CNTF, bFGF or IGF-1 were delivered to the host retina by adeno-associated virus type 2 (AAV2/2) viral vectors 4 weeks prior to cell transplantation; an AAV2/2 vector encoding a red fluorescent protein reporter construct was used as a control. Cells from dissociated P3 neural retinas were transplanted subretinally. At 3 weeks post-injection, the number of integrated, differentiated photoreceptor cells present in growth factor treated eyes, was compared to the control treated contralateral eye.

Results: : Increased levels of secreted CNTF protein in the host retina led to a significant decrease in the number of integrated photoreceptor cells. Similarly, increased bFGF expression had adverse effects, both on the number of integrated photoreceptors and the survival of unintegrated cells in the subretinal space. Conversely, more integrated cells were observed in the IGF-1 treated eyes, compared to contralateral controls. Examination of control eyes demonstrated that AAV2/2 vector administration had no detrimental effects on precursor cell integration.

Conclusions: : Here, we show that photoreceptor precursor cell integration can be modulated by ectopic expression of growth factors in the adult host retinal environment. Increased levels of the neurotrophic factors, CNTF, bFGF and IGF-1, had differential effects on the transplantation and integration of photoreceptor precursor cells in the adult mouse. CNTF appears to play an inhibitory role in cell integration, possibly due to respecification of the donor cell population.

Keywords: transplantation • growth factors/growth factor receptors • photoreceptors 
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