Single-cell transcriptomics reveals maturation of transplanted stem cell–derived retinal pigment epithelial cells toward native state DOI Creative Commons
Bhav Harshad Parikh, Paul Blakeley,

Kakkad Regha

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(26)

Published: June 20, 2023

Transplantation of stem cell–derived retinal pigment epithelial (RPE) cells is considered a viable therapeutic option for age-related macular degeneration (AMD). Several landmark Phase I/II clinical trials have demonstrated safety and tolerability RPE transplants in AMD patients, albeit with limited efficacy. Currently, there understanding how the recipient retina regulates survival, maturation, fate specification transplanted cells. To address this, we into subretinal space immunocompetent rabbits 1 mo conducted single-cell RNA sequencing analyses on explanted monolayers, compared to their age-matched vitro counterparts. We observed an unequivocal retention identity, trajectory-inferred survival all populations after transplantation. Furthermore, was unidirectional maturation toward native adult human state RPE, regardless cell resource. Gene regulatory network analysis suggests that tripartite transcription factors ( FOS , JUND MAFF ) may be specifically activated posttransplanted cells, regulate canonical signature gene expression crucial supporting host photoreceptor function, prosurvival genes required RPE’s adaptation microenvironment. These findings shed insights transcriptional landscape transplantation, important implications cell-based therapy AMD.

Language: Английский

Non-syndromic retinitis pigmentosa DOI Creative Commons
Sanne K. Verbakel, Ramon A. C. van Huet, Camiel J. F. Boon

et al.

Progress in Retinal and Eye Research, Journal Year: 2018, Volume and Issue: 66, P. 157 - 186

Published: March 27, 2018

Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration rod and cone photoreceptors. RP is leading cause visual disability, with worldwide prevalence 1:4000. Although majority cases are non-syndromic, 20–30% patients also have an associated non-ocular condition. typically manifests night blindness in adolescence, followed concentric field loss, reflecting principal dysfunction photoreceptors; central vision loss occurs later life due to dysfunction. Photoreceptor function measured electroretinogram markedly reduced or even absent. Optical coherence tomography (OCT) fundus autofluorescence (FAF) imaging show progressive outer layers altered lipofuscin distribution characteristic pattern. Over past three decades, vast number disease-causing variants more than 80 genes been non-syndromic RP. The wide heterogeneity makes it challenging describe clinical findings pathogenesis. In this review, we provide comprehensive overview characteristics specific genetically defined patient subsets. We supply unique atlas color photographs most subtypes, discuss relevant considerations respect differential diagnoses. addition, involved pathogenesis RP, as well processes that affected pathogenic mutations these genes. Finally, review management strategies for including counseling, rehabilitation, current emerging therapeutic options.

Language: Английский

Citations

759
EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration DOI Open Access
Daisy Y. Shu, Erik Butcher, Magali Saint‐Geniez

et al.

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(12), P. 4271 - 4271

Published: June 16, 2020

Epithelial–mesenchymal transition (EMT) and endothelial–mesenchymal (EndMT) are physiological processes required for normal embryogenesis. However, these can be hijacked in pathological conditions to facilitate tissue fibrosis cancer metastasis. In the eye, EMT EndMT play key roles pathogenesis of subretinal fibrosis, end-stage age-related macular degeneration (AMD) that leads profound permanent vision loss. Predominant fibrotic lesions matrix-producing mesenchymal cells believed originate from retinal pigment epithelium (RPE) and/or choroidal endothelial (CECs) through EndMT, respectively. Recent evidence suggests RPE may also implicated during early stages AMD. Transforming growth factor-beta (TGFβ) is a cytokine orchestrating both EndMT. Investigations molecular mechanisms underpinning AMD have myriad contributing factors including signaling pathways, extracellular matrix remodelling, oxidative stress, inflammation, autophagy, metabolism mitochondrial dysfunction. Questions arise as differences derived two their distinct mechanistic contributions Detailed discussion on microenvironment highlights synergistic interactions between CECs augment vivo. Understanding differential regulatory networks dry wet forms aid development therapeutic strategies targeting potentially reverse aberrant cellular transdifferentiation processes, regenerate retina thus restore vision.

Language: Английский

Citations

207
Photoreceptor cells and RPE contribute to the development of diabetic retinopathy DOI

Deoye Tonade,

Timothy S. Kern

Progress in Retinal and Eye Research, Journal Year: 2020, Volume and Issue: 83, P. 100919 - 100919

Published: Nov. 12, 2020

Language: Английский

Citations

146
3D culture of human pluripotent stem cells in RGD-alginate hydrogel improves retinal tissue development DOI Creative Commons
Nicola C. Hunt, Dean Hallam,

Ayesha Karimi

et al.

Acta Biomaterialia, Journal Year: 2016, Volume and Issue: 49, P. 329 - 343

Published: Nov. 5, 2016

No treatments exist to effectively treat many retinal diseases. Retinal pigmented epithelium (RPE) and neural retina can be generated from human embryonic stem cells/induced pluripotent cells (hESCs/hiPSCs). The efficacy of current protocols is, however, limited. It was hypothesised that generation laminated and/or RPE hiPSCs/hESCs could enhanced by three dimensional (3D) culture in hydrogels. hiPSC- hESC-derived embryoid bodies (EBs) were encapsulated 0.5% RGD-alginate; 1% hyaluronic acid (HA) or HA/gelatin hydrogels maintained until day 45. Compared with controls (no gel), RGD-alginate increased: the percentage EBs foci; optic vesicles (OVs) simultaneously; area covered RPE; frequency (CRALBP+); expression markers (TYR RPE65) ganglion cell marker, MATH5. Furthermore, hydrogel encapsulation did not adversely affect other (PROX1, CRX, RCVRN, AP2α VSX2) as determined qRT-PCR, VSX2 positive flow cytometry. increased OVs RPE, but significantly influence any measures differentiation. HA-based had no significant effect on tissue development. results indicated derivation hESCs/hiPSCs hydrogel. This scaffold may useful for derivation, transport transplantation also enhance formation pigmented, epithelial tissue.The burden disease is ever growing increasing age world-wide population. Transplantation derived (PSCs) considered a promising treatment. However, PSCs using defined media lengthy process often variable between different lines. study alginate development PSCs, whereas acid-based not. first show 3D biomaterial improve PSCs. These findings indicate potential clinical application subsequent tissue. work have implications

Language: Английский

Citations

145
Bestrophinopathy: An RPE-photoreceptor interface disease DOI
Karina E Guziewicz,

Divya Sinha,

Néstor Más Gómez

et al.

Progress in Retinal and Eye Research, Journal Year: 2017, Volume and Issue: 58, P. 70 - 88

Published: Jan. 19, 2017

Language: Английский

Citations

102
In vitro and ex vivo models to study drug delivery barriers in the posterior segment of the eye DOI
Karen Peynshaert,

Joke Devoldere,

Stefaan C. De Smedt

et al.

Advanced Drug Delivery Reviews, Journal Year: 2017, Volume and Issue: 126, P. 44 - 57

Published: Sept. 20, 2017

Language: Английский

Citations

101
Phenotypic Spectrum of Pentosan Polysulfate Sodium–Associated Maculopathy DOI Open Access
Xiaodong Zhang, Stephen T. Armenti,

Stanford Taylor

et al.

JAMA Ophthalmology, Journal Year: 2019, Volume and Issue: 137(11), P. 1275 - 1275

Published: Sept. 5, 2019

A unique pigmentary maculopathy was recently described in 6 patients with long-term exposure to pentosan polysulfate sodium (PPS), a long-standing oral therapy for interstitial cystitis.To characterize the characteristics and clinical manifestations of PPS-associated maculopathy.In this multi-institutional case series, medical records who exhibited characteristic setting prior PPS were retrospectively reviewed. Data collected from August 1, 2012, October 2018, data analyzed 2018 January 2019.Drug exposure, visual acuity, retinal imaging characteristics.Of 35 included (70 eyes), 34 (97%) female, median (range) age 60 (37-79) years. The duration intake 15 (3-22) years, cumulative 1.61 (0.44-4.31) kg. leading symptoms metamorphopsia, blurred vision, prolonged dark adaptation. Median logMAR acuity all eyes 0.10 (-0.12 1.18). Fundus examination often revealed hyperpigmented macular spots (34 64 [53%]) interspersed pale-yellow deposits, although less commonly that pigment epithelial atrophy (6 26 [23%]; P < .001). Optical coherence tomography showed foci epithelium elevation or thickening associated hyperreflectance on near-infrared reflectance imaging. autofluorescence typically symmetric, confluent pattern hyperautofluorescent hypoautofluorescent involved fovea extended periphery 24 (36%). Longitudinal evaluation demonstrated dynamic changes abnormalities.These findings suggest is vision-threatening condition can manifest drug. Multimodal posits distinctive phenotype, characterized cohort by alterations within at epithelium-photoreceptor interface. Ongoing work might explore causality direct screening guidelines.

Language: Английский

Citations

99
Phagocytosis by the Retinal Pigment Epithelium: Recognition, Resolution, Recycling DOI Creative Commons
Whijin Kwon, Spencer A. Freeman

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: Nov. 13, 2020

Tissue-resident phagocytes are responsible for the routine binding, engulfment, and resolution of their meals. Such populations cells express appropriate surface receptors that tailored to recognize phagocytic targets niche initiate actin polymerization drives internalization. also harbour enzymes transporters along endocytic pathway orchestrate ingested macromolecules from phagolysosome. Solutes fluxed into cytosol can then be reutilized by phagocyte or exported use neighbouring cells. a fundamental metabolic coupling between resident tissue in which they reside is well-emphasized case retinal pigment epithelial (RPE) cells; specialized turnover photoreceptor outer segments (POS). Photoreceptors prone photo-oxidative damage long-term health depends enormously on disposal aged portions segment. The phagocytosis POS RPE sole means this clearance. themselves mitotically quiescent therefore must resolve material prevent toxic accumulation lysosome otherwise leads disorders. Here we describe sequence events underlying healthy photoreceptors with an emphasis signaling ensures distal transport solutes phagosome supersedes its resolution. While other systems may utilize different transporters, biophysical manifestations such expected apply all tissue-resident perform regular programs.

Language: Английский

Citations

97
The retinal pigment epithelium: Development, injury responses, and regenerative potential in mammalian and non-mammalian systems DOI
Stephanie M. George, Fangfang Lu, Mishal Rao

et al.

Progress in Retinal and Eye Research, Journal Year: 2021, Volume and Issue: 85, P. 100969 - 100969

Published: April 23, 2021

Language: Английский

Citations

63
Photoreceptor calyceal processes accompany the developing outer segment, adopting a stable length despite a dynamic core DOI Creative Commons
Maria Sharkova, Gonzalo Aparicio,

Constantin Mouzaaber

et al.

Journal of Cell Science, Journal Year: 2024, Volume and Issue: 137(7)

Published: March 13, 2024

ABSTRACT Vertebrate photoreceptors detect light through a large cilium-based outer segment, which is filled with photopigment-laden membranous discs. Surrounding the base of segment are microvilli-like calyceal processes (CPs). Although CP disruption has been associated altered morphology and photoreceptor degeneration, role CPs remains elusive. Here, we used zebrafish as model to characterize CPs. We quantified parameters report strong disparity in coverage between subtypes. length stable across dark conditions, yet heat-shock inducible expression tagged actin revealed rapid turnover core. Detailed imaging embryonic retina uncovered substantial remodeling developing apical surface, including transition from dynamic tangential vertically oriented immediately prior formation. Remarkably, also found direct connection extensions Müller glia retinal pigment epithelium, arranged bundles around ultraviolet sensitive cones. In summary, our data structure, development surrounding environment microvilli retina.

Language: Английский

Citations

10