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Tiago Santos-Ferreira, Kai Postel, Marius Ader; Cone-like photoreceptor transplantation into the mouse retina. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5817.
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© ARVO (1962-2015); The Authors (2016-present)
Vision impairment affects around 314 million people worldwide. In diurnal organisms, day vision depends on cone photoreceptors (PR) and several eye diseases including age-related macular degeneration, lead to cone PR degeneration. Several therapeutic approaches, such as gene and cell-therapy, are currently being developed mainly focusing on rod dystrophies, leaving cone-dystrophy therapies not well studied. Thus, we evaluated the feasibility of cone-like PR transplantation into wild type and diseased mouse retinas and the possibility of functional recovery.
Cone PR account for only 3% of the cells in the mouse retina. Hence, a more comprehensive source of cone PRs was developed. We crossed Nrl-/- mice, that contain no rods but only cone(-like) photoreceptors, with an actin GFP reporter line (aGFP). The resulting line tg(Nrl-/-,aGFP) was used as a source for cone-like PRs. Cone-like cells were sorted using Magnetic Associated Cell Sorting (MACS) using CD73 as a cell surface marker. Enriched CD73+ cells were transplanted into the subretinal space of adult wild-type (WT) retinas. Integration efficiency was analyzed 2 weeks after transplantation. Cone-like PRs were then transplanted into age matched cone dystrophy model (Cpfl1 mutant mice) and WT retinas. Integration rate and functional recovery (ERG measurements) were analyzed 4 weeks after transplantation.
The generated reporter line showed rosette-like structures typical of a rodless retina and expressed cone-specific markers. tg(Nrl-/-,aGFP) showed comparable ERG measurements to Nrl-/- mice. Cone-like PRs expressed CD73, which was used as a cell surface marker. MACS-CD73 sorted cone-like cells were able to integrate into WT hosts, having a peak of integration at post-natal day 4 (P4). Integrated cone-like cells are able to acquire a mature photoreceptor morphology. P4 MACS-CD73+ sorted cells were then transplanted into cpfl1 hosts, showing similar integration rates as in WT retinas and an increased a- and b-wave amplitudes under mesopic and photopic conditions.
Cone-like cells can integrate in different types of host retinas having a peak of integration at PN4. Cone-like cells express cone specific markers, acquire mature photoreceptor morphology and partially rescue daylight vision. Hence, cone-like cell transplantation might represent a promising strategy for the restoration of vision in cone-dystrophies.
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