Abstract
SummaryHuman vision relies heavily upon cone photoreceptors, and their loss results in permanent visual impairment. Transplantation of healthy photoreceptors can restore visual function in models of inherited blindness, a process previously understood to arise by donor cell integration within the host retina. However, we and others recently demonstrated that donor rod photoreceptors engage in material transfer with host photoreceptors, leading to the host cells acquiring proteins otherwise expressed only by donor cells. We sought to determine whether stem cell- and donor-derived cones undergo integration and/or material transfer. We find that material transfer accounts for a significant proportion of rescued cells following cone transplantation into non-degenerative hosts. Strikingly, however, substantial numbers of cones integrated into the Nrl−/− and Prph2rd2/rd2, but not Nrl−/−;RPE65R91W/R91W, murine models of retinal degeneration. This confirms the occurrence of photoreceptor integration in certain models of retinal degeneration and demonstrates the importance of the host environment in determining transplantation outcome.
Highlights
Loss of vision due to photoreceptor degeneration is a leading cause of blindness in the developed world, and replacing lost photoreceptors by the transplantation of healthy cells represents a promising therapeutic strategy
Transplantation of Donor- and Stem Cell-Derived Cone Precursors into Wild-Type Recipient Results in GFP+ Cells within Host outer nuclear layer (ONL) with Rod-like Morphologies We first assessed the outcomes of transplantation of cone photoreceptors isolated from a variety of donor- and stem cell-derived sources
L/MOpsin-GFP reporter virally labeled cones were derived from murine embryonic stem cell (ESC) retinal organoid cultures, as we have described previously (Kruczek et al, 2017; GonzalezCordero et al, 2013)
Summary
Loss of vision due to photoreceptor degeneration is a leading cause of blindness in the developed world, and replacing lost photoreceptors by the transplantation of healthy cells represents a promising therapeutic strategy. When transplanted into murine models of retinal disease, and if present in sufficiently large numbers, these cells have been shown to improve various measures of visual function (Barnea-Cramer et al, 2016; Singh et al, 2013; Barber et al, 2013; MacLaren et al, 2006; Pearson et al, 2012). Together, these findings demonstrate that transplanted donor rod photoreceptor cells have the potential to restore vision. The mixed nature of the Crx-GFP+ donor population presented the question of whether the preponderance of rod-like cells was due to plasticity in the fate of the donor photoreceptors (Siegert et al, 2012) or the result of more successful integration of the rod precursors present within the mixed population
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