1Division of Molecular Therapy, Institute of Ophthalmology, UCL, London, United Kingdom
2Developmental Biology Unit, Institute of Child Health, UCL, London, United Kingdom
3Division of Molecular Therapy, UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, United Kingdom
4NIHR Faculty, UCL/MEH London, United Kingdom
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.
Support: Medical Research Council UK, Fighting Blindess, Ireland, Royal Society UK, The Health Foundation UK
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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