scholarly journals Renormalization of metabolic coupling treats age-related degenerative disorders: an oxidative RPE niche fuels the more glycolytic photoreceptors

Eye ◽  
2022 ◽  
Author(s):  
Nicholas D. Nolan ◽  
Salvatore M. Caruso ◽  
Xuan Cui ◽  
Stephen H. Tsang
Keyword(s):  
Metabolic Pathways ◽  
Pigment Epithelium ◽  
Cell Types ◽  
Future Directions ◽  
Metabolic Coupling ◽  
Age Related ◽  
Degenerative Disorders ◽  
Metabolic Uncoupling ◽  
Retinal Degenerative Diseases ◽  
Suitable Area

AbstractRetinitis pigmentosa is characterized by a dysregulation within the metabolic coupling of the retina, particularly between the glycolytic photoreceptors and the oxidative retina pigment epithelium. This phenomenon of metabolic uncoupling is seen in both aging and retinal degenerative diseases, as well as across a variety of cell types in human biology. Given its crucial role in the health and maintenance of these cell types, the metabolic pathways involved present a suitable area for therapeutic intervention. Herein, this review covers the scope of this delicate metabolic interplay, its dysregulation, how it relates to the retina as well other cell types, and finally concludes with a summary of various strategies aimed at reinstating normal metabolic coupling within the retina, and future directions within the field.

scholarly journals Autophagy activated via GRP78 to alleviate endoplasmic reticulum stress for cell survival in blue light-mediated damage of A2E-laden RPEs

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jingyang Feng ◽  
Yuhong Chen ◽  
Bing Lu ◽  
Xiangjun Sun ◽  
Hong Zhu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Signaling Pathway ◽  
Blue Light ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Degenerative Diseases ◽  
Caspase 12 ◽  
Age Related ◽  
Retinal Degenerative Diseases

Abstract Background Retinal pigment epithelium cells (RPEs) are critical for maintaining retinal homeostasis. Accumulation of age-related lipofuscin, N-retinylidene-N-retinylethanolamine (A2E), makes RPEs vulnerable to blue light-mediated damage, which represents an initial cause of some retinal degenerative diseases. This study investigated the activation of autophagy and the signaling pathway involved in glucose-related protein 78 (GRP78) induced autophagy in blue light-mediated damage of A2E-laden RPEs. In addition, we explored whether autophagy could play a protective role by alleviating endoplasmic reticulum (ER) stress to promote RPEs survival. Methods RPEs were incubated with 25 μM A2E for 2 h and exposed to blue light for 20 min. The expression of ER stress-related apoptotic proteins, CHOP and caspase-12, as well as autophagy marker LC3 were measured by western blot analysis. Autophagosomes were observed by both transmission electron microscopy and immunofluorescence assays. GRP78 interference performed by short hairpin RNA (shRNA) was used to identify the signaling pathway involved in GRP78 induced autophagy. Cell death was assessed using TUNEL analysis. Results Treatment with A2E and blue light markedly increased the expression of ER stress-related apoptotic molecules CHOP and caspase-12. The activation of autophagy was recognized by observing autophagosomes at ultrastructural level. Additionally, punctate distributions of LC3 immunofluorescence and enhanced conversions of LC3-I to LC3-II were found in A2E and blue light-treated RPEs. Moreover, GRP78 interference reduced AMPK phosphorylation and promoted mTOR activity, thereby downregulating autophagy. In addition, the inhibition of autophagy made RPEs vulnerable to A2E and blue light damage. In contrast, the autophagy inducer rapamycin alleviated ER stress to promote RPEs survival. Conclusions GRP78 activates autophagy via AMPK/mTOR in blue light-mediated damage of A2E-laden RPEs in vitro. Autophagy may be a vital endogenous cytoprotective process to alleviate stress for RPEs survival in retinal degenerative diseases.

scholarly journals Stem cells: Aging and transcriptional fingerprints

2017 ◽  
Vol 217 (1) ◽  
pp. 79-92 ◽  
Author(s):  
Brice E. Keyes ◽  
Elaine Fuchs
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Function ◽  
Cell Types ◽  
Cell Populations ◽  
Functional Abilities ◽  
Future Directions ◽  
Age Related ◽  
Transcriptional Changes ◽  
Stem Cell Populations

Stem cells are imbued with unique qualities. They have the capacity to propagate themselves through symmetric divisions and to divide asymmetrically to engender new cells that can progress to differentiate into tissue-specific, terminal cell types. Armed with these qualities, stem cells in adult tissues are tasked with replacing decaying cells and regenerating tissue after injury to maintain optimal tissue function. With increasing age, stem cell functional abilities decline, resulting in reduced organ function and delays in tissue repair. Here, we review the effect of aging in five well-studied adult murine stem cell populations and explore age-related declines in stem cell function and their consequences for stem cell self-renewal, tissue homeostasis, and regeneration. Finally, we examine transcriptional changes that have been documented in aged stem cell populations and discuss new questions and future directions that this collection of data has uncovered.

Retinal Pigment Epithelium Regeneration by Induced Pluripotent Stem Cells; Therapeutic and Modelling Approaches on Retinal Degenerative Diseases

2021 ◽  
Vol 16 ◽  
Author(s):  
Shadi Setayeshi ◽  
Seyed Ahmad Rasoulinejad
Keyword(s):  
Retinal Pigment Epithelium ◽  
Disease Modeling ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Degenerative Diseases ◽  
Rpe Cells ◽  
Age Related ◽  
Retinal Degenerative Diseases ◽  
Epithelium Regeneration ◽  
Induced Pluripotent

Abstract: Retinal Degenerative Diseases [RDDs] are irreversible ocular damages categorized as retinopathies. RDDs affects about 0.05% of individuals worldwide. The degenerations of RPE cells are involved in inherited and age-related RDDs. After the invention of induced Pluripotent Stem Cell [iPSC] by Yamanaka, a promising window has been opened to regenerative medicine and disease modeling. Retinal pigment epithelium [RPE] degeneration related-RDDs are also affected by iPSCs. IPSC-derived RPE cells created a novel method for treating the RPE degeneration related-RDDs and retinal diseases modeling regarding finding a new therapeutic approach or drug development. There are various studies based on iPSC-derived RPE cells reporting the investigation of the role of a specific mutation, protein, signaling pathway, etc., responsible for a type of RDD. Furthermore, iPSC-based RPE therapy is expanded to include some clinical trials. Despite the incredible growth rate in iPSC-based studies in RPE-related diseases, there are some challenges, i.e., teratoma formation potential of iPSCs, the highly-cost procedure of iPSC-based regeneration of RPEs, lack of a universal protocol or cellular product applicable in all patients, etc. This article reviews the iPSC-based RPE generation and their therapeutic applications, studies on RPE-related molecular and cellular pathophysiologic features of RDD in the iPSC-based models, future perspectives, and the challenges ahead.

scholarly journals Neuronal Reprogramming for Tissue Repair and Neuroregeneration

2020 ◽  
Vol 21 (12) ◽  
pp. 4273 ◽  
Author(s):  
Roxanne Hsiang-Chi Liou ◽  
Thomas L. Edwards ◽  
Keith R. Martin ◽  
Raymond Ching-Bong Wong
Keyword(s):  
Regenerative Medicine ◽  
Neurological Diseases ◽  
Neuronal Cell ◽  
Cell Types ◽  
Cellular Reprogramming ◽  
Future Directions ◽  
Promising Target ◽  
Retinal Degenerative Diseases

Stem cell and cell reprogramming technology represent a rapidly growing field in regenerative medicine. A number of novel neural reprogramming methods have been established, using pluripotent stem cells (PSCs) or direct reprogramming, to efficiently derive specific neuronal cell types for therapeutic applications. Both in vitro and in vivo cellular reprogramming provide diverse therapeutic pathways for modeling neurological diseases and injury repair. In particular, the retina has emerged as a promising target for clinical application of regenerative medicine. Herein, we review the potential of neuronal reprogramming to develop regenerative strategy, with a particular focus on treating retinal degenerative diseases and discuss future directions and challenges in the field.

scholarly journals Mesenchymal Stem/Stromal Cells and Fibroblasts: Their Roles in Tissue Injury and Regeneration, and Age-Related Degeneration

2021 ◽  
Author(s):  
Janja Zupan
Keyword(s):  
Stromal Cells ◽  
Tissue Injury ◽  
Cell Types ◽  
Common Features ◽  
Normal Tissues ◽  
Structural Framework ◽  
Age Related ◽  
Degenerative Disorders ◽  
Health And Disease ◽  
Almost All

Mesenchymal stem/stromal cells (MSCs) and fibroblasts are present in normal tissues to support tissue homeostasis. Both share common pathways and have a number of common features, such as a spindle-shaped morphology, connective tissue localization, and multipotency. In inflammation, a nonspecific response to injury, fibroblasts and MSC are the main players.Two mechanisms of their mode of action have been defined: immunomodulation and regeneration. Following tissue injury, MSCs are activated, and they multiply and differentiate, to mitigate the damage. With aging and, in particular, in degenerative disorders of the musculoskeletal system (i.e., joint and bone disorders), the regenerative capacity of MSCs appears to be lost or diverted into the production of other nonfunctional cell types, such as adipocytes and fibroblasts. Fibroblasts are stromal cells that provide the majority of the structural framework of almost all types of tissues; i.e., the stroma. As such, fibroblasts also have significant roles in tissue development, maintenance, and repair. In their immunosuppressive role, MSCs and fibroblasts contribute to the normal resolution of inflammation that is a prerequisite for successful tissue repair. In this chapter, we review the common and opposing properties of different tissue-derived MSCs and fibroblasts under physiological and pathophysiological conditions. We consider injury and age-related degeneration of various tissues, and also some immunological disorders. Specifically, we address the distinct and common features of both cell types in health and disease, with a focus on human synovial joints. Finally, we also discuss the possible approaches to boost the complementary roles of MSCs and fibroblasts, to promote successful tissue regeneration.

scholarly journals Cell-Type-Specific Complement Profiling in the ABCA4−/− Mouse Model of Stargardt Disease

2020 ◽  
Vol 21 (22) ◽  
pp. 8468
Author(s):  
Yassin Jabri ◽  
Josef Biber ◽  
Nundehui Diaz-Lezama ◽  
Antje Grosche ◽  
Diana Pauly
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Disease ◽  
Cell Loss ◽  
Cell Types ◽  
Retinal Cell ◽  
Complement Factor ◽  
Complement Inhibitors ◽  
Age Related ◽  
Abca4 Gene

Stargardt macular degeneration is an inherited retinal disease caused by mutations in the ATP-binding cassette subfamily A member 4 (ABCA4) gene. Here, we characterized the complement expression profile in ABCA4−/− retinae and aligned these findings with morphological markers of retinal degeneration. We found an enhanced retinal pigment epithelium (RPE) autofluorescence, cell loss in the inner retina of ABCA4−/− mice and demonstrated age-related differences in complement expression in various retinal cell types irrespective of the genotype. However, 24-week-old ABCA4−/− mice expressed more c3 in the RPE and fewer cfi transcripts in the microglia compared to controls. At the protein level, the decrease of complement inhibitors (complement factor I, CFI) in retinae, as well as an increased C3b/C3 ratio in the RPE/choroid and retinae of ABCA4−/−, mice was confirmed. We showed a corresponding increase of the C3d/C3 ratio in the serum of ABCA4−/− mice, while no changes were observed for CFI. Our findings suggest an overactive complement cascade in the ABCA4−/− retinae that possibly contributes to pathological alterations, including microglial activation and neurodegeneration. Overall, this underpins the importance of well-balanced complement homeostasis to maintain retinal integrity.

scholarly journals Nanocarriers, Progenitor Cells, Combinational Approaches, and New Insights on the Retinal Therapy

2021 ◽  
Vol 22 (4) ◽  
pp. 1776
Author(s):  
Elham Pishavar ◽  
Hongrong Luo ◽  
Johanna Bolander ◽  
Antony Atala ◽  
Seeram Ramakrishna
Keyword(s):  
Drug Delivery ◽  
Progenitor Cells ◽  
Transfection Efficiency ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Therapeutic Approaches ◽  
Age Related ◽  
Nanofibrous Scaffolds ◽  
The Stability

Progenitor cells derived from the retinal pigment epithelium (RPECs) have shown promise as therapeutic approaches to degenerative retinal disorders including diabetic retinopathy, age-related macular degeneration and Stargardt disease. However, the degeneration of Bruch’s membrane (BM), the natural substrate for the RPE, has been identified as one of the major limitations for utilizing RPECs. This degeneration leads to decreased support, survival and integration of the transplanted RPECs. It has been proposed that the generation of organized structures of nanofibers, in an attempt to mimic the natural retinal extracellular matrix (ECM) and its unique characteristics, could be utilized to overcome these limitations. Furthermore, nanoparticles could be incorporated to provide a platform for improved drug delivery and sustained release of molecules over several months to years. In addition, the incorporation of tissue-specific genes and stem cells into the nanostructures increased the stability and enhanced transfection efficiency of gene/drug to the posterior segment of the eye. This review discusses available drug delivery systems and combination therapies together with challenges associated with each approach. As the last step, we discuss the application of nanofibrous scaffolds for the implantation of RPE progenitor cells with the aim to enhance cell adhesion and support a functionally polarized RPE monolayer.

scholarly journals Role of amyloid β-peptide in the pathogenesis of age-related macular degeneration

2021 ◽  
Vol 6 (1) ◽  
pp. e000774
Author(s):  
Minwei Wang ◽  
Shiqi Su ◽  
Shaoyun Jiang ◽  
Xinghuai Sun ◽  
Jiantao Wang
Keyword(s):  
Mitochondrial Dysfunction ◽  
Macular Degeneration ◽  
Vision Loss ◽  
Cell Structure ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Amyloid Β ◽  
Age Related Macular Degeneration ◽  
Amyloid Β Peptide ◽  
Age Related

Age-related macular degeneration (AMD) is the most common eye disease in elderly patients, which could lead to irreversible vision loss and blindness. Increasing evidence indicates that amyloid β-peptide (Aβ) might be associated with the pathogenesis of AMD. In this review, we would like to summarise the current findings in this field. The literature search was done from 1995 to Feb, 2021 with following keywords, ‘Amyloid β-peptide and age-related macular degeneration’, ‘Inflammation and age-related macular degeneration’, ‘Angiogenesis and age-related macular degeneration’, ‘Actin cytoskeleton and amyloid β-peptide’, ‘Mitochondrial dysfunction and amyloid β-peptide’, ‘Ribosomal dysregulation and amyloid β-peptide’ using search engines Pubmed, Google Scholar and Web of Science. Aβ congregates in subretinal drusen of patients with AMD and participates in the pathogenesis of AMD through enhancing inflammatory activity, inducing mitochondrial dysfunction, altering ribosomal function, regulating the lysosomal pathway, affecting RNA splicing, modulating angiogenesis and modifying cell structure in AMD. The methods targeting Aβ are shown to inhibit inflammatory signalling pathway and restore the function of retinal pigment epithelium cells and photoreceptor cells in the subretinal region. Targeting Aβ may provide a novel therapeutic strategy for AMD.

scholarly journals 4-(Phenylsulfanyl) Butan-2-One Attenuates the Inflammatory Response Induced by Amyloid-β Oligomers in Retinal Pigment Epithelium Cells

Marine Drugs ◽  
2020 ◽  
Vol 19 (1) ◽  
pp. 1
Author(s):  
Peeraporn Varinthra ◽  
Shun-Ping Huang ◽  
Supin Chompoopong ◽  
Zhi-Hong Wen ◽  
Ingrid Y. Liu
Keyword(s):  
Retinal Pigment Epithelium ◽  
Inflammatory Response ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Amyloid Β ◽  
Age Related Macular Degeneration ◽  
Epithelial Cell Line ◽  
Age Related ◽  
Tnf Α ◽  
Cox 2

Age-related macular degeneration (AMD) is a progressive eye disease that causes irreversible impairment of central vision, and effective treatment is not yet available. Extracellular accumulation of amyloid-beta (Aβ) in drusen that lie under the retinal pigment epithelium (RPE) has been reported as one of the early signs of AMD and was found in more than 60% of Alzheimer’s disease (AD) patients. Extracellular deposition of Aβ can induce the expression of inflammatory cytokines such as IL-1β, TNF-α, COX-2, and iNOS in RPE cells. Thus, finding a compound that can effectively reduce the inflammatory response may help the treatment of AMD. In this research, we investigated the anti-inflammatory effect of the coral-derived compound 4-(phenylsulfanyl) butan-2-one (4-PSB-2) on Aβ1-42 oligomer (oAβ1-42) added to the human adult retinal pigment epithelial cell line (ARPE-19). Our results demonstrated that 4-PSB-2 can decrease the elevated expressions of TNF-α, COX-2, and iNOS via NF-κB signaling in ARPE-19 cells treated with oAβ1-42 without causing any cytotoxicity or notable side effects. This study suggests that 4-PSB-2 is a promising drug candidate for attenuation of AMD.

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