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Donor and host photoreceptors engage in material transfer following transplantation of post-mitotic photoreceptor precursors

2016-10-04 19:39:34

Nature Communications; 4 October 2016: DOI:10.1038/ncomms13029

R. A. Pearson, A. Gonzalez-Cordero, E. L. West, J. R. Ribeiro, N. Aghaizu, D. Goh, R. D. Sampson, A. Georgiadis, P. V. Waldron, Y. Duran, A. Naeem, M. Kloc, E. Cristante, K. Kruczek, K. Warre-Cornish, J. C. Sowden, A. J. Smith & R. R. Ali



Abstract


Photoreceptor replacement by transplantation is proposed as a treatment for blindness. Transplantation of healthy photoreceptor precursor cells into diseased murine eyes leads to the presence of functional photoreceptors within host retinae that express an array of donor-specific proteins. The resulting improvement in visual function was understood to be due to donor cells integrating within host retinae. Here, however, we show that while integration occurs the majority of donor-reporter-labelled cells in the host arises as a result of material transfer between donor and host photoreceptors. Material transfer does not involve permanent donor–host nuclear or cell–cell fusion, or the uptake of free protein or nucleic acid from the extracellular environment. Instead, RNA and/or protein are exchanged between donor and host cells in vivo. These data require a re-evaluation of the mechanisms underlying rescue by photoreceptor transplantation and raise the possibility of material transfer as a strategy for the treatment of retinal disorders.



Introduction


Transplantation of healthy donor cells into diseased environments is a promising therapeutic strategy for a wide range of diseases. In the eye, despite different underlying causes, many degenerative disorders lead to the loss of the light-sensitive photoreceptors and blindness. At present, few clinically available treatments are capable of reversing this. Clinical trials for gene-supplementation therapy have shown promise for patients with known genetic defects but photoreceptor replacement by transplantation is proposed as a broad treatment strategy applicable to many forms of retinal degeneration. Photoreceptor replacement could be useful during the degenerative process, when some host photoreceptors remain, for diseases with an unknown aetiology. Alternatively, cell therapy may be applied as a treatment for end-stage disease, when little, if any, of the outer nuclear layer (ONL) of the host retina remains.



We, and others, have shown previously that the transplantation of stage-specific post-mitotic rod photoreceptor precursors carrying a transgenic green fluorescent protein (GFP) label results in the presence of GFP-positive (GFP+) rod-like cells within the ONL where photoreceptors normally reside, in wild-type and degenerating murine host retinae. These cells bear the morphological characteristics of mature photoreceptors, including synapse-like structures and outer segments. Importantly, when transplanted into different models of retinal degeneration, GFP+ cells within the host ONL demonstrated robust levels of those proteins that were genetically absent in the host photoreceptors. Moreover, single-cell12 and whole-retinal recordings showed these GFP+ cells to be light-responsive in a manner very similar to that of normal wild-type photoreceptors. The presence of these cells also correlated with visually evoked activity in the visual cortex and behaviour, when present in sufficiently large numbers. Strikingly, the developmental stage of the donor cell at the time of transplantation is important; transplantation of embryonic or adult photoreceptors led to poor integration of cells within the host ONL a finding that holds true for both postnatally derived donor cells and photoreceptor precursors derived from three-dimensional (3D) differentiation of embryonic stem (ES) cells. Altogether, these data provided evidence of robust rescue of photoreceptor function following the transplantation of healthy photoreceptors.



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Key Words

Regenerative medicine | Retina | Stem cells