In Pursuit of Authenticity: Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium for Clinical Applications

Miyagishima, Kiyoharu; Wan, Qin; Corneo, Barbara; Sharma, Ruchi; Lotfi, Mostafa; Boles, Nathan C.; Fang, Hua; Maminishkis, Arvydas; Zhang, Congxiao; Blenkinsop, Timothy A.; Khristov, Vladimir; Jha, Balendu Shekhar; Memon, Omar; D’Souza, Sunita L.; Temple, Sally; Miller, Sheldon S.; Bharti, Kapil

doi:10.5966/sctm.2016-0037

Cited by 85 publications

(83 citation statements)

References 61 publications

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“…Our observations suggest a clear involvement of genetic susceptibility towards AMD, notably in the inflammatory and complement factors associated with AMD pathogenesis. The tissue of origin (cornea or RPE) was not the same for all hiPSC-RPE lines which could result in some epigenetic differences; however, in a recent study, we found that such different originating tissues did not affect hiPSC-RPE phenotype or functionality (Miyagishima et al, 2016), and we found no significant differences related to tissue of origin or to cell passage. Some AMD-associated factors did not show significant differences between AMD and control lines, but these could emerge if oxidative stressors (Rabin et al, 2013) or complement components such as C1q (Johnson et al, 2011) or molecules that accelerate aging such as progerin (Miller et al, 2013) were added.…”

Section: Discussioncontrasting

confidence: 56%

Nicotinamide Ameliorates Disease Phenotypes in a Human iPSC Model of Age-Related Macular Degeneration

et al. 2017

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Summary Age-related macular degeneration (AMD) affects the retinal pigment epithelium (RPE), a cell monolayer essential for photoreceptor survival, and is the leading cause of vision loss in the elderly. There are no disease-altering therapies for dry AMD, which is characterized by accumulation of subretinal drusen deposits and complement-driven inflammation. We report the derivation of human induced pluripotent stem cells (hiPSCs) from patients diagnosed with AMD, including two with the rare ARMS2/HTRA1 homozygous genotype. The hiPSC-derived RPE cells produce several AMD/drusen-related proteins, and those from AMD donors showed significantly increased complement and inflammatory factors, most exaggerated in ARMS2/HTRA1 lines. Using a panel of AMD biomarkers and candidate drug screening, combined with transcriptome analysis, we discovered that Nicotinamide (NAM) ameliorated disease-related phenotypes by inhibiting drusen proteins, inflammatory and complement factors, while upregulating nucleosome, ribosome and chromatin-modifying genes. Thus, targeting NAM-regulated pathways is a promising avenue for developing therapeutics to combat AMD.

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Section: Discussioncontrasting

confidence: 56%

Nicotinamide Ameliorates Disease Phenotypes in a Human iPSC Model of Age-Related Macular Degeneration

et al. 2017

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“…Having diverse phenotypes in the training set enhanced the robustness of the algorithms, as was expected from the literature (18). Additionally, the method worked on 2 different donors, not only as an end-point assay of tissue health, but also as a noninvasive tool for tracking tissue development during the long maturation period (approximately 35 days) (33). Importantly, the accuracy of the algorithms in predicting both TER and VEGFratio was close to the measurement uncertainty for both TER (31) and VEGF (30,34).…”

Section: Discussionmentioning

confidence: 88%

Deep learning predicts function of live retinal pigment epithelium from quantitative microscopy

Schaub¹,

Hotaling²,

Manescu³

et al. 2020

Journal of Clinical Investigation

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“…However, much is still not understood about the genetic characteristics of stem cell‐derived RPE or its behavior after transplantation . Furthermore, there is only limited information about the functionality of ion channels and Ca 2+ signaling in stem cell‐derived RPE. In particular, studies about the voltage‐gated Ca 2+ (Ca V ) channels in these cells are lacking.…”

Section: Introductionmentioning

confidence: 99%

Functional Voltage-Gated Calcium Channels Are Present in Human Embryonic Stem Cell-Derived Retinal Pigment Epithelium

Korkka

Viheriälä

Juuti‐Uusitalo

et al. 2018

Stem Cells Translational Medicine

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Retinal pigment epithelium (RPE) performs important functions for the maintenance of photoreceptors and vision. Malfunctions within the RPE are implicated in several retinal diseases for which transplantations of stem cell‐derived RPE are promising treatment options. Their success, however, is largely dependent on the functionality of the transplanted cells. This requires correct cellular physiology, which is highly influenced by the various ion channels of RPE, including voltage‐gated Ca2+ (CaV) channels. This study investigated the localization and functionality of CaV channels in human embryonic stem cell (hESC)‐derived RPE. Whole‐cell patch‐clamp recordings from these cells revealed slowly inactivating L‐type currents comparable to freshly isolated mouse RPE. Some hESC‐RPE cells also carried fast transient T‐type resembling currents. These findings were confirmed by immunostainings from both hESC‐ and mouse RPE that showed the presence of the L‐type Ca2+ channels CaV1.2 and CaV1.3 as well as the T‐type Ca2+ channels CaV3.1 and CaV3.2. The localization of the major subtype, CaV1.3, changed during hESC‐RPE maturation co‐localizing with pericentrin to the base of the primary cilium before reaching more homogeneous membrane localization comparable to mouse RPE. Based on functional assessment, the L‐type Ca2+ channels participated in the regulation of vascular endothelial growth factor secretion as well as in the phagocytosis of photoreceptor outer segments in hESC‐RPE. Overall, this study demonstrates that a functional machinery of voltage‐gated Ca2+ channels is present in mature hESC‐RPE, which is promising for the success of transplantation therapies. stem cells translational medicine 2019;8:179&15

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In Pursuit of Authenticity: Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium for Clinical Applications

Cited by 85 publications

References 61 publications

Nicotinamide Ameliorates Disease Phenotypes in a Human iPSC Model of Age-Related Macular Degeneration

Nicotinamide Ameliorates Disease Phenotypes in a Human iPSC Model of Age-Related Macular Degeneration

Deep learning predicts function of live retinal pigment epithelium from quantitative microscopy

Functional Voltage-Gated Calcium Channels Are Present in Human Embryonic Stem Cell-Derived Retinal Pigment Epithelium

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