Human Induced Pluripotent Stem Cells As a Tool to Model a Form of Leber Congenital Amaurosis

Lustremant, Céline; Habeler, Walter; Plancheron, Alexandra; Goureau, Olivier; Grenot, Lydie; Grange, Pierre de la; Audo, Isabelle; Nandrot, Emeline F.; Monville, Christelle

doi:10.1089/cell.2012.0076

Cited by 32 publications

(17 citation statements)

References 87 publications

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“…This implies that stress degree can determine the level of NNAT expression in photoreceptors. Our finding with rat models of retinitis pigmentosa correlates with the data obtained with fibroblasts isolated from patients with Leber congenital amaurosis (LCA), in that NNAT was found to be up-regulated (Lustremant et al, 2013). This fact provides a link between activated ER stress response contributing to the pathogenesis of the LCA (Zhang et al, 2012) and over-expression of NNAT.…”

Section: Discussionsupporting

confidence: 87%

Neuronatin is a stress-responsive protein of rod photoreceptors

et al. 2016

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Neuronatin (NNAT) is a small transmembrane proteolipid that is highly expressed in the embryonic developing brain and several other peripheral tissues. This study is the first to provide evidence that NNAT is detected in the adult retina of various adult rod-dominant mammals, including wild-type (WT) rodents, transgenic rodents expressing mutant S334ter, P23H, or T17M rhodopsin, non-human primates, humans, and cone-dominant tree shrews. Immunohistochemical and quantitative real time polymerase chain reaction (qRT-PCR) analyses were applied to detect NNAT. Confocal microscopy analysis revealed that NNAT immunofluorescence is restricted to the outer segments (OSs) of photoreceptors without evidence of staining in other retinal cell types across all mammalian species. Moreover, in tree shrew retinas, we found NNAT to be co-localized with rhodopsin, indicating its predominant expression in rods. The rod-derived expression of NNAT was further confirmed by qRT-PCR in isolated rod photoreceptor cells. We also used these cells to mimic cellular stress in transgenic retinas by treating them with the endoplasmic reticulum stress inducer, tunicamycin. Thus, our data revealed accumulation of NNAT around the nucleus as compared to dispersed localization of NNAT within control cells. This distribution coincided with the partial intracellular mislocalization of NNAT to the outer nuclear layer observed in transgenic retinas. In addition, stressed retinas demonstrated an increase of NNAT mRNA and protein levels. Therefore, our study demonstrated that NNAT is a novel stress-responsive protein with a potential structural and/or functional role in adult mammalian retinas.

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Section: Discussionsupporting

confidence: 87%

Neuronatin is a stress-responsive protein of rod photoreceptors

et al. 2016

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“…Recently, Jin et al generated a retinitis pigmentosa (RP) cell model from iPSCs by initially deriving iPSC lines from the fibroblast cells of five RP patients with distinct mutations in the RP1, RP9, PRPH2, or RHO genes. The iPSCs were then differentiated into rod photoreceptor cells (Jin et al, 2009) in which markers of oxidative and endoplasmic reticulum stress were studied (Lustremant et al, 2013).…”

Section: Ipsc-rpementioning

confidence: 99%

Stem cell based therapies for age-related macular degeneration: The promises and the challenges

Nazari

Zhang

Zhu

et al. 2015

Progress in Retinal and Eye Research

177

142

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Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. AMD is classified as either neovascular (NV-AMD) or non-neovascular (NNV-AMD). Cumulative damage to the retinal pigment epithelium, Bruch's membrane, and choriocapillaris leads to dysfunction and loss of RPE cells. This causes degeneration of the overlying photoreceptors and consequential vision loss in advanced NNV-AMD (Geographic Atrophy). In NV-AMD, abnormal growth of capillaries under the retina and RPE, which leads to hemorrhage and fluid leakage, is the main cause of photoreceptor damage. Although a number of drugs (e.g., anti-VEGF) are in use for NV-AMD, there is currently no treatment for advanced NNV-AMD. However, replacing dead or dysfunctional RPE with healthy RPE has been shown to rescue dying photoreceptors and improve vision in animal models of retinal degeneration and possibly in AMD patients. Differentiation of RPE from human embryonic stem cells (hESC-RPE) and from induced pluripotent stem cells (iPSC-RPE) has created a potentially unlimited source for replacing dead or dying RPE. Such cells have been shown to incorporate into the degenerating retina and result in anatomic and functional improvement. However, major ethical, regulatory, safety, and technical challenges have yet to be overcome before stem cell-based therapies can be used in standard treatments. This review outlines the current knowledge surrounding the application of hESC-RPE and iPSC-RPE in AMD. Following an introduction on the pathogenesis and available treatments of AMD, methods to generate stem cell-derived RPE, immune reaction against such cells, and approaches to deliver desired cells into the eye will be explored along with broader issues of efficacy and safety. Lastly, strategies to improve these stem cell-based treatments will be discussed.

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“…Lustremant et al [76] examined the transcriptomics of human iPSC-derived neural stem cells and RPE from two patients with Leber congenital amaurosis (LCA). Although the pathogenic mutation was not known, they showed changes in the expression of 21 genes when compared to wild-type controls.…”

Section: Clinical Use Of Patient-specific Ipsc-derived Retinal Cellsmentioning

confidence: 99%

iPS Cells for Modelling and Treatment of Retinal Diseases

Chen

McLenachan

Edel

et al. 2014

JCM

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For many decades, we have relied on immortalised retinal cell lines, histology of enucleated human eyes, animal models, clinical observation, genetic studies and human clinical trials to learn more about the pathogenesis of retinal diseases and explore treatment options. The recent availability of patient-specific induced pluripotent stem cells (iPSC) for deriving retinal lineages has added a powerful alternative tool for discovering new disease-causing mutations, studying genotype-phenotype relationships, performing therapeutics-toxicity screening and developing personalised cell therapy. This review article provides a clinical perspective on the current and potential benefits of iPSC for managing the most common blinding diseases of the eye: inherited retinal diseases and age-related macular degeneration.

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Human Induced Pluripotent Stem Cells As a Tool to Model a Form of Leber Congenital Amaurosis

Cited by 32 publications

References 87 publications

Neuronatin is a stress-responsive protein of rod photoreceptors

Neuronatin is a stress-responsive protein of rod photoreceptors

Stem cell based therapies for age-related macular degeneration: The promises and the challenges

iPS Cells for Modelling and Treatment of Retinal Diseases

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