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


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
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    • "Using iPSC technology to create the autologous source for cell therapy is an attractive strategy for regenerative medicine. Currently, most of the iPSC-based cell therapies are still tested in laboratory animal models, such as sickle cell anemia[103], spinal cord injury[104,105], age-related macular degeneration (AMD)[106], Parkinson's disease[107,108], and in non-human primates109110111112113. However, it has been demonstrated that human iPSCs could be used as a source of retinal pigment epithelial (RPE) cells for the treatment of AMD114115116. "
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    ABSTRACT: Background: Nuclear reprogramming with pluripotency factors enables somatic cells to gain the properties of embryonic stem cells. Mitochondrial resetting and metabolic reprogramming are suggested to be key early events in the induction of human skin fibroblasts to induced pluripotent stem cells (iPSCs). Scope of review: We review recent advances in the study of the molecular basis for mitochondrial resetting and metabolic reprogramming in the regulation of the formation of iPSCs. In particular, the recent progress in using iPSCs for mitochondrial disease modeling was discussed. Major conclusions: iPSCs rely on glycolysis rather than oxidative phosphorylation as a major supply of energy. Mitochondrial resetting and metabolic reprogramming thus play crucial roles in the process of generation of iPSCs from somatic cells. General significance: Neurons, myocytes, and cardiomyocytes are cells containing abundant mitochondria in the human body, which can be differentiated from iPSCs or trans-differentiated from fibroblasts. Generating these cells from iPSCs derived from skin fibroblasts of patients with mitochondrial diseases or by trans-differentiation with cell-specific transcription factors will provide valuable insights into the role of mitochondrial DNA heteroplasmy in mitochondrial disease modeling and serves as a novel platform for screening of drugs to treat patients with mitochondrial diseases.
    Full-text · Article · Jan 2016 · Biochimica et Biophysica Acta (BBA) - General Subjects
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    • "A recent followup study of the 18 patients involved in the trials revealed no serious safety issues related to the transplanted cells (Schwartz et al., 2015). Implantation of a single layer of stem-cell-derived RPE is another treatment approach currently under development (Carr et al., 2013; Idelson et al., 2009). Recently, a Japanese woman in her 70s was the first person to receive a transplanted layer of iPSC-RPE derived from her own skin cells (Cyranoski, 2014). "
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    ABSTRACT: Age-related macular degeneration (AMD) is a complex neurodegenerative visual disorder that causes profound physical and psychosocial effects. Visual impairment in AMD is caused by the loss of retinal pigmented epithelium (RPE) cells and the light-sensitive photoreceptor cells that they support. There is currently no effective treatment for the most common form of this disease (dry AMD). A new approach to treating AMD involves the transplantation of RPE cells derived from either human embryonic or induced pluripotent stem cells. Multiple clinical trials are being initiated using a variety of cell therapies. Although many animal models are available for AMD research, most do not recapitulate all aspects of the disease, hampering progress. However, the use of cultured RPE cells in AMD research is well established and, indeed, some of the more recently described RPE-based models show promise for investigating the molecular mechanisms of AMD and for screening drug candidates. Here, we discuss innovative cell-culture models of AMD and emerging stem-cell-based therapies for the treatment of this vision-robbing disease. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Apr 2015 · Disease Models and Mechanisms
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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.
    Full-text · Article · Feb 2015 · Stem Cell Research
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