Transfer of cell material by photoreceptor transplantation: mechanisms and implications on therapy development

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Pre-clinical studies provided evidence for successful photoreceptor cell replacement therapy. Migration and integration of donor photoreceptors into the host retinal tissue has been proposed as the underlying mechanism for restored visual function. However, recent results reveal that donor photoreceptors do not structurally integrate into the retinal tissue but instead reside at the injection site between the photoreceptor layer and the retinal pigment epithelium, the so called subretinal space, and exchange cytoplasmic material with host photoreceptors. By combining single cell analysis, Cre/LoxP technology, and independent labelling of cytoplasm and nucleus we reliably tracked allogeneic transplants demonstrating for the first time transfer of cytoplasmic content between graft and host photoreceptors without nuclear translocation. This unexpected interaction of donor with host photoreceptors represents a paradigm shift in the photoreceptor transplantation field and has vital implications on photoreceptor replacement approaches, as the majority of studies published on this topic within the last decade will have to be re-interpreted. Although the mechanism of vision improvement by photoreceptor transplantation may be different than originally conceptualized, capitalizing on the exchange of intracellular material may represent a productive novel route for future therapeutic strategies. Therefore, we will decipher components and mechanisms involved in the material transfer between donor and host cells by assessing (i) the potential of different cell types for exchange of cellular material in the retina, (ii) the cellular components that are transferred between donor and host cells, (iii) potential mechanisms of cytoplasmic exchange, (iv) the influence of outer segment affecting retinopathies on material transfer, and (v) whether pluripotent stem cell-derived photoreceptors show a similar potential for transfer of intercellular components. The expected results will be of utmost importance for the development of novel therapy approaches aiming to repair dysfunctional photoreceptors and thus visual function.