Utility of Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium for an In Vitro Model of Proliferative Vitreoretinopathy

Greene, Whitney; Kaini, Ramesh; Wang, Heuy-Ching

doi:10.1007/978-3-030-28471-8_2

Cited by 6 publications

(5 citation statements)

References 151 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…iPSC-derived cells from patients with complex diseases have been shown to exhibit disease-specific phenotypes in vitro and these cells could bridge the gap between clinical phenotype and molecular, cellular mechanisms [9,17,18,[35][36][37]. Established culture protocols for iPSC-derived cells ensure that sufficient numbers of cells are available to conduct meaningful experiments, thereby creating a new, disease-specific platform for the identification of new mechanisms and revealing underlying pathways of disease [38].…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of Inflammasome-Related Genes in Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells with or without History of Age-Related Macular Degeneration

Hytti

Korhonen

Hongisto

et al. 2021

IJMS

View full text Add to dashboard Cite

Inflammation is a key underlying factor of age-related macular degeneration (AMD) and inflammasome activation has been linked to disease development. Induced pluripotent stem-cell-derived retinal pigment epithelial cells (iPSC-RPE) are an attractive novel model system that can help to further elucidate disease pathways of this complex disease. Here, we analyzed the effect of dysfunctional protein clearance on inflammation and inflammasome activation in iPSC-RPE cells generated from a patient suffering from age-related macular degeneration (AMD) and an age-matched control. We primed iPSC-RPE cells with IL-1α and then inhibited both proteasomal degradation and autophagic clearance using MG-132 and bafilomycin A1, respectively, causing inflammasome activation. Subsequently, we determined cell viability, analyzed the expression levels of inflammasome-related genes using a PCR array, and measured the levels of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and MCP-1 secreted into the medium. Cell treatments modified the expression of 48 inflammasome-related genes and increased the secretion of mature IL-1β, while reducing the levels of IL-6 and MCP-1. Interestingly, iPSC-RPE from an AMD donor secreted more IL-1β and expressed more Hsp90 prior to the inhibition of protein clearance, while MCP-1 and IL-6 were reduced at both protein and mRNA levels. Overall, our results suggest that cellular clearance mechanisms might already be dysfunctional, and the inflammasome activated, in cells with a disease origin.

show abstract

Section: Discussionmentioning

confidence: 99%

Differential Expression of Inflammasome-Related Genes in Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells with or without History of Age-Related Macular Degeneration

Hytti

Korhonen

Hongisto

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…These models have also been used to investigate the cell contractile properties using collagen matrix contraction assays [27,39]. Surprisingly, it has been reported that exposition to normal vitreous fluid during wound healing tends to increase the fibrotic response of hiPSC-derived RPE cells [40].…”

Section: Emt Induction Through Mechanical Stimulationmentioning

confidence: 99%

“…Furthermore, hiPSC can be obtained from human with minimally invasive techniques, such as skin biopsy or blood sampling [27,41]. However, hiPSC culture and differentiation into RPE cells is costly and time-consuming, whether the differentiation is spontaneous or guided, therefore limiting its use in routine research [40,49].…”

Section: Advantages and Limitations Of In Vitro Pvr Modelsmentioning

confidence: 99%

Experimental Models to Study Epithelial-Mesenchymal Transition in Proliferative Vitreoretinopathy

Datlibagi

Zein-El-Din

Frohly

et al. 2023

IJMS

View full text Add to dashboard Cite

Proliferative vitreoretinal diseases (PVDs) encompass proliferative vitreoretinopathy (PVR), epiretinal membranes, and proliferative diabetic retinopathy. These vision-threatening diseases are characterized by the development of proliferative membranes above, within and/or below the retina following epithelial-mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) and/or endothelial-mesenchymal transition of endothelial cells. As surgical peeling of PVD membranes remains the sole therapeutic option for patients, development of in vitro and in vivo models has become essential to better understand PVD pathogenesis and identify potential therapeutic targets. The in vitro models range from immortalized cell lines to human pluripotent stem-cell-derived RPE and primary cells subjected to various treatments to induce EMT and mimic PVD. In vivo PVR animal models using rabbit, mouse, rat, and swine have mainly been obtained through surgical means to mimic ocular trauma and retinal detachment, and through intravitreal injection of cells or enzymes to induce EMT and investigate cell proliferation and invasion. This review offers a comprehensive overview of the usefulness, advantages, and limitations of the current models available to investigate EMT in PVD.

show abstract

“…Proliferative vitreoretinopathy (PVR) is a disease that arises as a complication of rhegmatogenous retinal detachment, is characterized by the formation of subretinal or epiretinal membranes, and can lead to vision loss or severe blindness [ 1 ]. PVR occurs in 5–10% of retinal detachment cases, and surgical treatment is the main current therapy, but recurrence occurs readily after the operation [ 2 ]. Retinal pigment epithelium (RPE) cells are the principal cell components within the PVR membranes, and epithelial–mesenchymal transition (EMT) in these cells is considered the hallmark of PVR pathogenesis [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

DAPL1 prevents epithelial–mesenchymal transition in the retinal pigment epithelium and experimental proliferative vitreoretinopathy

Han

Liu

et al. 2023

Cell Death Dis

View full text Add to dashboard Cite

Epithelial–mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is a hallmark of the pathogenesis of proliferative vitreoretinopathy (PVR) that can lead to severe vision loss. Nevertheless, the precise regulatory mechanisms underlying the pathogenesis of PVR remain largely unknown. Here, we show that the expression of death-associated protein-like 1 (DAPL1) is downregulated in PVR membranes and that DAPL1 deficiency promotes EMT in RPE cells in mice. In fact, adeno-associated virus (AAV)-mediated DAPL1 overexpression in RPE cells of Dapl1-deficient mice inhibited EMT in physiological and retinal-detachment states. In a rabbit model of PVR, ARPE-19 cells overexpressing DAPL1 showed reduced ability to induce experimental PVR, and AAV-mediated DAPL1 delivery attenuated the severity of experimental PVR. Furthermore, a mechanistic study revealed that DAPL1 promotes P21 phosphorylation and its stabilization partially through NFκB (RelA) in RPE cells, whereas the knockdown of P21 led to neutralizing effects on DAPL1-dependent EMT inhibition and enhanced the severity of experimental PVR. These results suggest that DAPL1 acts as a novel suppressor of RPE-EMT and has an important role in antagonizing the pathogenesis of experimental PVR. Hence, this finding has implications for understanding the mechanism of and potential therapeutic applications for PVR.

show abstract

Utility of Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium for an In Vitro Model of Proliferative Vitreoretinopathy

Cited by 6 publications

References 151 publications

Differential Expression of Inflammasome-Related Genes in Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells with or without History of Age-Related Macular Degeneration

Differential Expression of Inflammasome-Related Genes in Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells with or without History of Age-Related Macular Degeneration

Experimental Models to Study Epithelial-Mesenchymal Transition in Proliferative Vitreoretinopathy

DAPL1 prevents epithelial–mesenchymal transition in the retinal pigment epithelium and experimental proliferative vitreoretinopathy

Contact Info

Product

Resources

About