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    • Surgical transplantation Algvere et al

    2018-11-08

    Surgical transplantation (Algvere et al., 1997) or translocation (van Meurs and Van Den Biesen, 2003) of RPE sheets into the macula preserves central vision, providing proof of concept that RPE transplantation can be beneficial in AMD (reviewed in Binder et al., 2007). Stem cell technology now provides ample sources of RPE VE-822 for transplantation to counteract RPE cell loss in AMD. Pluripotent stem cells (PSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells have been successfully differentiated into RPE (Buchholz et al., 2009; Klimanskaya et al., 2004), and early stage clinical trials transplanting ESC-derived RPE suspensions report safety and preliminary benefit (Schwartz et al., 2012, 2015; Song et al., 2015). An important concern with PSC-derived RPE is the possibility of overgrowth and mis-differentiation due to residual undifferentiated source cells; this has been addressed by extensive differentiation into the RPE phenotype prior to transplantation (Kanemura et al., 2014). The influence of RPE differentiation stage on transplant efficacy, however, has not been described. We used an adult RPE stem cell, which is less plastic than PSC and does not form tumors, to determine the influence of RPE differentiation stage on transplant outcome. The human RPE layer contains a minor subpopulation of cells that by stringent clonal analyses and other tests fulfill the criteria of stem cells, namely they can self-renew and produce differentiated progeny; these are adult RPE stem cells (RPESCs) (Salero et al., 2012). RPESCs are poised to generate highly pure cultures of RPE progeny (RPESC-RPE) displaying characteristics of native RPE (Blenkinsop et al., 2015). We previously reported that subretinal transplantation of RPESC-RPE in the Royal College of Surgeons (RCS) rat prevents the loss of photoreceptor cells that occurs in these animals (Davis et al., 2016). Here, we report that transplantation of RPESC-RPE effectively rescued vision (i.e., prevented vision loss that normally occurs in the RCS rat) in a differentiation stage-dependent manner. Specifically, transplantation of an intermediate 4-week stage of RPE differentiation most consistently preserved vision.
    Results
    Discussion Stem cell-derived RPE cells are being advanced into the clinic as a cell replacement therapy for AMD and related blinding disorders. We report that the stage of RPE differentiation influences the ability of transplanted RPE to rescue vision. Correlation of transplant efficacy with an intermediate stage of development has been reported for other cell types, such as photoreceptor cells (MacLaren et al., 2006), glia (Warrington et al., 1993), and dopaminergic neurons (Brundin et al., 1986; Ganat et al., 2012). Consistent with the prior findings using other cell types, our results indicate that transplanting an intermediate progenitor stage of RPE differentiation improves transplant efficacy for vision rescue. RPESC derived from human donor eyes differentiate into mature RPE over a period of several weeks in culture. During this time, cells undergo continuous changes in morphology, proliferation rate, polarization, and acquisition of key RPE phenotypic characteristics (Blenkinsop et al., 2013, 2015; Salero et al., 2012; Stanzel et al., 2014). The features of maturing RPE cells responsible for the improved ability to rescue vision at 4 weeks remain to be uncovered. However, here we report the finding that the phagocytic activity of RPESC-RPE declines after 4 weeks of maturation, which is also the time of maximum efficacy at vision rescue. This correlation raises the possibility that phagocytic activity may contribute to the stage dependence of vision rescue. Phagocytic ability was not significantly different between the 2- and 4-week stages, however, indicating that this alone could not explain the differences in efficacy at vision rescue. Although much remains to be learned about the mechanisms that confer improved efficacy to less differentiated cells, improved migration, integration, and continued differentiation after transplantation are thought to influence the ability of transplanted stem cell progeny to replace host tissue (Conboy et al., 2015). The possibility that intermediate RPE progenitor states engraft and survive better than mature cells has potential impact on decisions whether to implant RPE as a scaffold (Diniz et al., 2013) or as a suspension (Schwartz et al., 2012), because if a particular stage of RPE cells integrates well, they may not need to be delivered on a scaffold in order to replace the host RPE monolayer. Future studies will be aimed at identifying the mechanisms that confer transplant efficacy to specific stages of RPESC development.