Protective Effects of Human iPS-Derived Retinal Pigment Epithelium Cell Transplantation in the Retinal Dystrophic Rat

Department of Ocular Biology and Therapeutics, Institute of Ophthalmology, University College London, London, United Kingdom.
PLoS ONE (Impact Factor: 3.23). 12/2009; 4(12):e8152. DOI: 10.1371/journal.pone.0008152
Source: PubMed

ABSTRACT Transformation of somatic cells with a set of embryonic transcription factors produces cells with the pluripotent properties of embryonic stem cells (ESCs). These induced pluripotent stem (iPS) cells have the potential to differentiate into any cell type, making them a potential source from which to produce cells as a therapeutic platform for the treatment of a wide range of diseases. In many forms of human retinal disease, including age-related macular degeneration (AMD), the underlying pathogenesis resides within the support cells of the retina, the retinal pigment epithelium (RPE). As a monolayer of cells critical to photoreceptor function and survival, the RPE is an ideally accessible target for cellular therapy. Here we report the differentiation of human iPS cells into RPE. We found that differentiated iPS-RPE cells were morphologically similar to, and expressed numerous markers of developing and mature RPE cells. iPS-RPE are capable of phagocytosing photoreceptor material, in vitro and in vivo following transplantation into the Royal College of Surgeons (RCS) dystrophic rat. Our results demonstrate that iPS cells can be differentiated into functional iPS-RPE and that transplantation of these cells can facilitate the short-term maintenance of photoreceptors through phagocytosis of photoreceptor outer segments. Long-term visual function is maintained in this model of retinal disease even though the xenografted cells are eventually lost, suggesting a secondary protective host cellular response. These findings have identified an alternative source of replacement tissue for use in human retinal cellular therapies, and provide a new in vitro cellular model system in which to study RPE diseases affecting human patients.

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Available from: Amanda-Jayne Carr, Sep 27, 2015
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    • "ESC/iPSC can be induced to predominantly differentiate into RPE cells using similar protocols as above, but with the omission/antagonism of FGF to bias the generation of RPE cells over neural retina (Meyer et al., 2009, Osakada et al., 2009a). These ESC/iPSCderived RPE cells phagocytise photoreceptor outer segments(Carr et al., 2009a) and preserve retinal function in the RCS rats(Vugler et al., 2008, Carr et al., 2009b). A study comparing adult human ESC-derived RPE with foetal human RPE demonstrated a strong correlation in their gene expression profiles. "
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    ABSTRACT: Stem cell therapies are being explored extensively as treatments for degenerative eye disease, either for replacing lost neurons, restoring neural circuits or, based on more recent evidence, as paracrine-mediated therapies in which stem cell-derived trophic factors protect compromised endogenous retinal neurons from death and induce the growth of new connections. Retinal progenitor phenotypes induced from embryonic stem cells/induced pluripotent stem cells (ESCs/iPSCs) and endogenous retinal stem cells may replace lost photoreceptors and retinal pigment epithelial (RPE) cells and restore vision in the diseased eye, whereas treatment of injured retinal ganglion cells (RGCs) has so far been reliant on mesenchymal stem cells (MSC). Here, we review the properties of non-retinal-derived adult stem cells, in particular neural stem cells (NSCs), MSC derived from bone marrow (BMSC), adipose tissues (ADSC) and dental pulp (DPSC), together with ESC/iPSC and discuss and compare their potential advantages as therapies designed to provide trophic support, repair and replacement of retinal neurons, RPE and glia in degenerative retinal diseases. We conclude that ESCs/iPSCs have the potential to replace lost retinal cells, whereas MSC may be a useful source of paracrine factors that protect RGC and stimulate regeneration of their axons in the optic nerve in degenerate eye disease. NSC may have potential as both a source of replacement cells and also as mediators of paracrine treatment. Copyright © 2015. Published by Elsevier B.V.
    Stem Cell Research 02/2015; 2(3). DOI:10.1016/j.scr.2015.02.003 · 3.69 Impact Factor
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    • "Autologous somatic cells can be genetically reprogrammed into induced pluripotent stem cells (iPSCs), an embryonic stem cell-like state, and then differentiate into all three germ layer cells, including a retinal lineage with the production of photoreceptors and RPE cells [7]. These iPSCs derived cells have been transplanted into animal models of retinal degeneration and have shown promising results [8], [9]. Whilst using this differentiation method, risk of tumour formation remains due to contamination with undifferentiated cells [10]. "
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    ABSTRACT: The Corneal limbus is a readily accessible region at the front of the eye, separating the cornea and sclera. Neural colonies (neurospheres) can be generated from adult corneal limbus in vitro. We have previously shown that these neurospheres originate from neural crest stem/progenitor cells and that they can differentiate into functional neurons in vitro. The aim of this study was to investigate whether mouse and human limbal neurosphere cells (LNS) could differentiate towards a retinal lineage both in vivo and in vitro following exposure to a developing retinal microenvironment. In this article we show that LNS can be generated from adult mice and aged humans (up to 97 years) using a serum free culture assay. Following culture with developing mouse retinal cells, we detected retinal progenitor cell markers, mature retinal/neuronal markers and sensory cilia in the majority of mouse LNS experiments. After transplantation into the sub-retinal space of neonatal mice, mouse LNS cells expressed photoreceptor specific markers, but no incorporation into host retinal tissue was seen. Human LNS cells also expressed retinal progenitor markers at the transcription level but mature retinal markers were not observed in vitro or in vivo. This data highlights that mouse corneal limbal stromal progenitor cells can transdifferentiate towards a retinal lineage. Complete differentiation is likely to require more comprehensive regulation; however, the accessibility and plasticity of LNS makes them an attractive cell resource for future study and ultimately therapeutic application.
    PLoS ONE 10/2014; 9(10):e108418. DOI:10.1371/journal.pone.0108418 · 3.23 Impact Factor
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    • "The dystrophic RCS rat has a mutation in a gene crucial for photoreceptor outer segment phagocytosis (Mertk), which results in primary loss of RPE and secondary photoreceptor degradation. Similar to studies using hESC-RPE and other retinal and non-retinal cell types (Gamm et al., 2007; Idelson et al., 2009; Lund et al., 2006; McGill et al., 2007; Wang et al., 2008), injection of dissociated hiPSC-RPE into the subretinal space of RCS rats resulted in long-term photoreceptor survival and retention of visual function (Carr et al., 2009). Similarly, Li et al. treated 2 day postnatal SCID Rpe65 rd12 /Rpe65 rd12 mice with a subretinal bolus of hiPSC-RPE and showed that donor cells integrated into the host RPE. "
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    ABSTRACT: Human pluripotent stem cells have made a remarkable impact on science, technology and medicine by providing a potentially unlimited source of human cells for basic research and clinical applications. In recent years, knowledge gained from the study of human embryonic stem cells and mammalian somatic cell reprogramming has led to the routine production of human induced pluripotent stem cells (hiPSCs) in laboratories worldwide. hiPSCs show promise for use in transplantation, high throughput drug screening, "disease-in-a-dish" modeling, disease gene discovery, and gene therapy testing. This review will focus on the first application, beginning with a discussion of methods for producing retinal lineage cells that are lost in inherited and acquired forms of retinal degenerative disease. The selection of appropriate hiPSC-derived donor cell type(s) for transplantation will be discussed, as will the caveats and prerequisite steps to formulating a clinical Good Manufacturing Practice (cGMP) product for clinical trials.
    Experimental Eye Research 06/2014; 123. DOI:10.1016/j.exer.2013.12.001 · 2.71 Impact Factor
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