Epithelial–mesenchymal transition‐related serum markers ET‐1, IL‐8 and TGF‐β2 are elevated in a Finnish wet age‐related macular degeneration cohort

Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in the elderly population. In our previous studies, we found that deficiency of CXCR5 causes AMD-like pathological phenotypes in mice, characterized by abnormalities and dysfunction of the retinal pigment epithelium (RPE) cells. The abnormalities included abnormal cellular shape and impaired barrier function. In the present study, primary RPE cells were derived separately from CXCR5 knockout (KO) mice and from C57BL6 wild type (WT). The isolated primary cells were cultured for several days, and then total RNA was isolated and used for library preparation, sequencing, and the resultant raw data analyzed. Relative to the WT, a total of 1392 differentially expressed genes (DEG) were identified. Gene ontology analysis showed various biological processes, cellular components, and molecular functions were enriched. Pathway enrichment analysis revealed several pathways, including the PI3K-Akt signaling, mTOR signaling, FoxO, focal adhesion, endocytosis, ubiquitin-mediated proteolysis, TNFα-NF-kB Signaling, adipogenesis genes, p53 signaling, Ras, autophagy, epithelial–mesenchymal transition (EMT), and mitochondrial pathway. This study explores molecular signatures associated with deficiency of CXCR5 in RPE cells. Many of these signatures are important for homeostasis of this tissue. The identified pathways and genes require further evaluation to better understand the pathophysiology of AMD.

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EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration

International Journal of Molecular Sciences ◽

10.3390/ijms21124271 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4271 ◽

Cited By ~ 4

Author(s):

Daisy Y. Shu ◽

Erik Butcher ◽

Magali Saint-Geniez

Keyword(s):

Macular Degeneration ◽

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Transforming Growth Factor ◽

Retinal Pigment ◽

Mesenchymal Cells ◽

Age Related Macular Degeneration ◽

Mesenchymal Transition ◽

Age Related

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

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Nanoceria Particles Are an Eligible Candidate to Prevent Age-Related Macular Degeneration by Inhibiting Retinal Pigment Epithelium Cell Death and Autophagy Alterations

Cells ◽

10.3390/cells9071617 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1617 ◽

Cited By ~ 4

Author(s):

Annamaria Tisi ◽

Vincenzo Flati ◽

Simona Delle Monache ◽

Luca Lozzi ◽

Maurizio Passacantando ◽

...

Keyword(s):

Cell Death ◽

Retinal Pigment Epithelium ◽

Macular Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Cellular Damage ◽

Mesenchymal Transition ◽

Rpe Cells ◽

Age Related

Retinal pigment epithelium (RPE) dysfunction and degeneration underlie the development of age-related macular degeneration (AMD), which is the leading cause of blindness worldwide. In this study, we investigated whether cerium oxide nanoparticles (CeO2-NPs or nanoceria), which are anti-oxidant agents with auto-regenerative properties, are able to preserve the RPE. On ARPE-19 cells, we found that CeO2-NPs promoted cell viability against H2O2–induced cellular damage. For the in vivo studies, we used a rat model of acute light damage (LD), which mimics many features of AMD. CeO2-NPs intravitreally injected three days before LD prevented RPE cell death and degeneration and nanoceria labelled with fluorescein were found localized in the cytoplasm of RPE cells. CeO2-NPs inhibited epithelial-mesenchymal transition of RPE cells and modulated autophagy by the down-regulation of LC3B-II and p62. Moreover, the treatment inhibited nuclear localization of LC3B. Taken together, our study demonstrates that CeO2-NPs represent an eligible candidate to counteract RPE degeneration and, therefore, a powerful therapy for AMD.

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Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22041684 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1684

Author(s):

Janusz Blasiak ◽

Ali Koskela ◽

Elzbieta Pawlowska ◽

Mikko Liukkonen ◽

Johanna Ruuth ◽

...

Keyword(s):

Epithelial Mesenchymal Transition ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Cell Contact ◽

Peroxisome Proliferator ◽

Filamentous Actin ◽

Knock Out ◽

Mesenchymal Transition ◽

Age Related

Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness worldwide in the elderly population. In our previous studies, we found that deficiencies in the nuclear factor, erythroid 2 like 2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) genes caused AMD-like pathological phenotypes in mice. In the present work, we show hijacked epithelial-mesenchymal transition (EMT) due to the common loss of PGC-1α and NFE2L2 (double knock-out, dKO) genes in aged animals. The implanted area was assessed by histology, immunohistochemistry and transmission electron microscopy. Confocal microscopy revealed altered regions in the filamentous actin ring. This contrasted with hexagonal RPE morphology in wild-type mice. The ultrastructural RPE features here illustrated loss of apical microvilli, alteration of cell-cell contact, loss of basal in-folding with deposits on Bruch’s membrane, and excessive lipofuscin deposition in dKO samples. We also found the expression of epithelial-mesenchymal transition transcription factors, such as Snail, Slug, collagen 1, vimentin and OB-cadherin, to be significantly different in dKO RPEs. An increased immunoreactivity of senescence markers p16, DEC1 and HMGB1 was also noted. These findings suggest that EMT and senescence pathways may intersect in the retinas of dKO mice. Both processes can be activated by damage to the RPE, which may be caused by increased oxidative stress resulting from the absence of NFE2L2 and PGC-1α genes, important for antioxidant defense. This dKO model may provide useful tools for studying AMD pathogenesis and evaluating novel therapies for this disease.

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AMD-Like Substrate Causes Epithelial Mesenchymal Transition in iPSC-Derived Retinal Pigment Epithelial Cells Wild Type but Not C3-Knockout

International Journal of Molecular Sciences ◽

10.3390/ijms22158183 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8183

Author(s):

Blanca Chinchilla ◽

Rosario Fernandez-Godino

Keyword(s):

Epithelial Mesenchymal Transition ◽

Retinal Pigment ◽

Retinal Pigment Epithelial Cells ◽

Age Related Macular Degeneration ◽

Mesenchymal Transition ◽

Rpe Cells ◽

Genetic Ablation ◽

Medical Needs ◽

Sequence Of Events ◽

Age Related

The Bruch’s membrane (BrM) is a five-layered extracellular matrix (ECM) that supports the retinal pigment epithelium (RPE). Normal age-related changes in the BrM may lead to RPE cell damage and ultimately to the onset and progression of age-related macular degeneration (AMD), which is the most common cause of visual loss among the elderly. A role for the complement system in AMD pathology has been established, but the disease mechanisms are poorly understood, which hampers the design of efficient therapies to treat millions of patients. In an effort to identify the mechanisms that lead from normal aging to pathology, we have developed a cell-based model using complement deficient human induced pluripotent stem cell (iPSC)-derived RPE cells cultured on an AMD-like ECM that mimics BrM. The data present evidence that changes in the ECM result in loss of differentiation and promote epithelial mesenchymal transition (EMT) of healthy RPE cells. This pathological process is mediated by complement activation and involves the formation of a randomly oriented collagen meshwork that drives the dedifferentiation of the RPE monolayer. Genetic ablation of complement component 3 has a protective effect against EMT but does not prevent the abnormal deposition of collagens. These findings offer new insights into the sequence of events that initiate AMD and may guide the design of efficient therapies to treat this disease with unmet medical needs.

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The Regulation of NFE2L2 (NRF2) Signalling and Epithelial-to-Mesenchymal Transition in Age-Related Macular Degeneration Pathology

International Journal of Molecular Sciences ◽

10.3390/ijms20225800 ◽

2019 ◽

Vol 20 (22) ◽

pp. 5800 ◽

Cited By ~ 7

Author(s):

Hyttinen ◽

Kannan ◽

Felszeghy ◽

Niittykoski ◽

Salminen ◽

...

Keyword(s):

Macular Degeneration ◽

Epithelial To Mesenchymal Transition ◽

Retinal Pigment ◽

Developed Countries ◽

Cellular Systems ◽

Age Related Macular Degeneration ◽

Cellular Damage ◽

Related Factor ◽

Mesenchymal Transition ◽

Age Related

Age-related macular degeneration (AMD) is a mounting cause of loss of sight in the elderly in the developed countries, a trend enhanced by the continual ageing of the population. AMD is a multifactorial and only partly understood, malady. Unfortunately, there is no effective treatment for most AMD patients. It is known that oxidative stress (OS) damages the retinal pigment epithelium (RPE) and contributes to the progression of AMD. We review here the potential importance of two OS-related cellular systems in relation to AMD. First, the nuclear factor erythroid 2-related factor 2 (NFE2L2; NRF2)-mediated OS response signalling pathway is important in the prevention of oxidative damage and a failure of this system could be critical in the development of AMD. Second, epithelial-to-mesenchymal transition (EMT) represents a change in the cellular phenotype, which ultimately leads to the fibrosis encountered in RPE, a characteristic of AMD. Many of the pathways triggering EMT are promoted by OS. The possible interconnections between these two signalling routes are discussed here. From a broader perspective, the control of NFE2L2 and EMT as ways of preventing OS-derived cellular damage could be potentially valuable in the therapy of AMD.

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7-ketocholesterol induces endothelial-mesenchymal transition and promotes fibrosis: implications in neovascular age-related macular degeneration and treatment

Angiogenesis ◽

10.1007/s10456-021-09770-0 ◽

2021 ◽

Author(s):

Haibo Wang ◽

Aniket Ramshekar ◽

Eric Kunz ◽

M. Elizabeth Hartnett

Keyword(s):

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Mesenchymal Transition ◽

Age Related ◽

Endothelial Mesenchymal Transition

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Age related macular degeneration (ARMD) – pathophysiological and clinical features and therapeutic concepts

Therapeutische Umschau ◽

10.1024/0040-5930.58.1.28 ◽

2001 ◽

Vol 58 (1) ◽

pp. 28-35 ◽

Cited By ~ 1

Author(s):

Ursula Körner-Stiefbold

Keyword(s):

Macular Degeneration ◽

Clinical Features ◽

Altersbedingte Makuladegeneration ◽

Age Related Macular Degeneration ◽

Genetische Faktoren ◽

Age Related ◽

Therapeutic Concepts

Die altersbedingte Makuladegeneration (AMD) ist eine der häufigsten Ursachen für einen irreversiblen Visusverlust bei Patienten über 65 Jahre. Nahezu 30% der über 75-Jährigen sind von einer AMD betroffen. Trotz neuer Erkenntnisse in der Grundlagenforschung ist die Ätiologie, zu der auch genetische Faktoren gehören, noch nicht völlig geklärt. Aus diesem Grund sind die Behandlungsmöglichkeiten zum jetzigen Zeitpunkt noch limitiert, so dass man lediglich von Therapieansätzen sprechen kann. Die derzeit zur Verfügung stehenden Möglichkeiten wie medikamentöse, chirurgische und laser- und strahlentherapeutische Maßnahmen werden beschrieben.

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