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Jane C. Sowden, Michael Baron, Jorn Lakowski, Ya-Ting Han, James W. Bainbridge, Rachael A. Pearson, Robin R. Ali; The Adult Retinal Environment Favours New Rod Cell Integration And Limits Cone Cell Differentiation Following Transplantation Of Crx.gfp Precursor Cells. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5895.
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Retinal degenerative conditions result in the irrevocable loss of rod and cone photoreceptors. Replacing the lost photoreceptors by cell transplantation offers a potential future treatment as immature rod precursor cells can integrate into the diseased murine retina and restore some visual function. Since human visual acuity relies mainly on the less prevalent cone photoreceptor we sought to determine the transplantation competence of immature cone precursors.
Crx (cone-rod homeobox), a key regulator of photoreceptor development, is expressed in post-mitotic rod and cone cells. Immature precursors expressing a Crx.gfp transgene were isolated from developing retinae by flow cytometry at embryonic and postnatal stages where the majority of cells are specified to become cones or rods respectively. Precursors were transplanted into adult wildtype and degenerating retinae and levels of integrated cone and rod photoreceptors within the outer nuclear layer (ONL) were analysed.
Embryonic-stage Crx.gfp precursors migrated into the recipient ONL and 1-3% differentiated into new cones, whereas >97% differentiated into new rods in the adult environment. BrdU birthdating indicated that at this same stage > 90% of newborn Crx.gfp cells develop as cones in the developing retina. New cone cells displayed characteristic cone morphological features and expressed RxRγ and cone arrestin. By contrast postnatal-stage Crx.gfp precursors generated new integrated rods with a ten fold higher efficiency.
Crx.gfp precursor cells develop into cone and rod photoreceptors after transplantation into the adult wildtype and degenerating retina in ratios similar to that of the host retina (1:35) even when the transplanted population consisted primarily of cone precursors. Like in the late stages of retinal histogenesis when rod specification is dominant, the adult retina presents a permissive environment for new rod integration and differentiation but limits the number of new integrating and differentiating cones.
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