Effects of senescent secretory phenotype acquisition on human retinal pigment epithelial stem cells

Lazzarini, Raffaella; Nicolai, Michele; Pirani, Vittorio; Mariotti, Cesare; Primio, Roberto Di

doi:10.18632/aging.101624

Cited by 9 publications

(3 citation statements)

References 56 publications

(63 reference statements)

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“…MMPs and their inhibitors play a role in the pathogenesis of AMD [ 108 ] [ 109 , 110 ] by reorganizing the extracellular matrix [ 111 ] and reduction in the build up of sub-RPE material [ 58 ]. CDKN1A is involved in RPE differentiation, proliferation, migration, and cell-cycle progression [ 112 ]. As such, CDKN1A plays a role in the ageing process of RPE and hence in AMD [ 113 ].…”

Section: Discussionmentioning

confidence: 99%

A Multi-Omics Approach Identifies Key Regulatory Pathways Induced by Long-Term Zinc Supplementation in Human Primary Retinal Pigment Epithelium

et al. 2020

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In age-related macular degeneration (AMD), both systemic and local zinc levels decline. Elevation of zinc in clinical studies delayed the progression to end-stage AMD. However, the molecular pathways underpinning this beneficial effect are not yet identified. In this study, we used differentiated primary human fetal retinal pigment epithelium (RPE) cultures and long-term zinc supplementation to carry out a combined transcriptome, proteome and secretome analysis from three genetically different human donors. After combining significant differences, we identified the complex molecular networks using Database for Annotation, Visualization and Integrated Discovery (DAVID) and Ingenuity Pathway Analysis (IPA). The cell cultures from the three donors showed extensive pigmentation, development of microvilli and basal infoldings and responded to zinc supplementation with an increase in transepithelial electrical resistance (TEER) (apical supplementation: 443.2 ± 79.3%, basal supplementation: 424.9 ± 116.8%, compared to control: 317.5 ± 98.2%). Significant changes were observed in the expression of 1044 genes, 151 cellular proteins and 124 secreted proteins. Gene set enrichment analysis revealed changes in specific molecular pathways related to cell adhesion/polarity, extracellular matrix organization, protein processing/transport, and oxidative stress response by zinc and identified a key upstream regulator effect similar to that of TGFB1.

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“…A main feature of SASP is the presence of cytokines and chemokines whose expression is regulated by NF-κB [ 47 ]. In our experimental model, the long-term exposure to H 2 O 2 increased the expression of the inflammatory cytokines IL-6 and IL-1β thus suggesting the acquisition of SASP, which could also affect other retinal cells during pathogenesis and progression of AMD [ 9 , 48 ]. Moreover, the increase in pro-inflammatory mediators upon senescence induction may mirror inflammaging, a state of low-grade chronic inflammation induced by age-related mitochondrial dysfunction that is deeply connected to age-relate pathologies including AMD [ 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between Long-Term Sublethal Oxidative Stress and Detrimental Inflammation as Potential Drivers for Age-Related Retinal Degeneration

et al. 2020

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Age-related retinal degenerations, including age-related macular degeneration (AMD), are caused by the loss of retinal pigmented epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD, deeply linked to the aging process, also involves oxidative stress and inflammatory responses. However, the molecular mechanisms contributing to the shift from healthy aging to AMD are still poorly understood. Since RPE cells in the retina are chronically exposed to a pro-oxidant microenvironment throughout life, we simulated in vivo conditions by growing ARPE-19 cells in the presence of 10 μM H2O2 for several passages. This long-term oxidative insult induced senescence in ARPE-19 cells without affecting cell proliferation. Global proteomic analysis revealed a dysregulated expression in proteins involved in antioxidant response, mitochondrial homeostasis, and extracellular matrix organization. The analyses of mitochondrial functionality showed increased mitochondrial biogenesis and ATP generation and improved response to oxidative stress. The latter, however, was linked to nuclear factor-κB (NF-κB) rather than nuclear factor erythroid 2–related factor 2 (Nrf2) activation. NF-κB hyperactivation also resulted in increased pro-inflammatory cytokines expression and inflammasome activation. Moreover, in response to additional pro-inflammatory insults, senescent ARPE-19 cells underwent an exaggerated inflammatory reaction. Our results indicate senescence as an important link between chronic oxidative insult and detrimental chronic inflammation, with possible future repercussions for therapeutic interventions.

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“…In the retina, senescent cells are often associated with age related diseases such as AMD, and their targeting in retinal pigmented epithelial (RPE) cells has shown success in reducing AMD-like phenotypes in animal models of AMD [43][44][45][46] . However, outside of the RPE, senescence of the inner retinal layers has seldom been investigated for its utility in contributing to regeneration of retinal neurons.…”

Section: Introductionmentioning

confidence: 99%

Damage-induced senescent immune cells regulate regeneration of the zebrafish retina

Konar

Flickinger

Sharma

et al. 2023

Preprint

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Zebrafish spontaneously regenerate their retina in response to damage through the action of Müller glia. Even though Müller glia (MG) are conserved in higher vertebrates, the capacity to regenerate retinal damage is lost. Recent work has focused on the regulation of inflammation during tissue regeneration with precise temporal roles for macrophages and microglia. Senescent cells that have withdrawn from the cell cycle have mostly been implicated in aging, but are still metabolically active, releasing pro-inflammatory signaling molecules as part of the Senescence Associated Secretory Phenotype (SASP). Here, we discover that in response to retinal damage, a subset of cells expressing markers of microglia/macrophages also express markers of senescence. These cells display a temporal pattern of appearance and clearance during retina regeneration. Premature removal of senescent cells by senolytic treatment led to a decrease in proliferation and incomplete repair of the ganglion cell layer after NMDA damage. Our results demonstrate a role for modulation of senescent cell responses to balance inflammation, regeneration, plasticity, and repair as opposed to fibrosis and scarring.

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Effects of senescent secretory phenotype acquisition on human retinal pigment epithelial stem cells

Cited by 9 publications

References 56 publications

A Multi-Omics Approach Identifies Key Regulatory Pathways Induced by Long-Term Zinc Supplementation in Human Primary Retinal Pigment Epithelium

Crosstalk between Long-Term Sublethal Oxidative Stress and Detrimental Inflammation as Potential Drivers for Age-Related Retinal Degeneration

Damage-induced senescent immune cells regulate regeneration of the zebrafish retina

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