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Retinal degenerative diseases result from oxidative stress and mitochondrial dysfunction, leading to the loss of visual acuity. Damaged retinal pigment epithelial (RPE) and photoreceptor cells undergo mitophagy. Pigment epithelium-derived factor (PEDF) protects from oxidative stress in RPE and improves mitochondrial functions. Overexpression of PEDF in placenta-derived mesenchymal stem cells (PD-MSCs; PD-MSCs PEDF ) provides therapeutic effects in retinal degenerative diseases. Here, we investigated whether PD-MSCs PEDF restored the visual cycle through a mitophagic mechanism in RPE cells in hydrogen peroxide (H 2 O 2 )-injured rat retinas. Compared with naïve PD-MSCs, PD-MSCs PEDF augmented mitochondrial biogenesis and translation markers as well as mitochondrial respiratory states. In the H 2 O 2 -injured rat model, intravitreal administration of PD-MSCs PEDF restored total retinal layer thickness compared to that of naïve PD-MSCs. In particular, PTEN-induced kinase 1 (PINK1), which is the major mitophagy marker, exhibited increased expression in retinal layers and RPE cells after PD-MSC PEDF transplantation. Similarly, expression of the visual cycle enzyme retinol dehydrogenase 11 (RDH11) showed the same patterns as PINK1 levels, resulting in improved visual activity. Taken together, these findings suggest that PD-MSCs PEDF facilitate mitophagy and restore the loss of visual cycles in H 2 O 2 -injured rat retinas and RPE cells. These data indicate a new strategy for next-generation MSC-based treatment of retinal degenerative diseases.

The use of multipotent mesenchymal stem cells (MSCs) has been reported as promising for the treatment of numerous degenerative disorders including the eye. In retinal degenerative diseases, MSCs exhibit the potential to regenerate into retinal neurons and retinal pigmented epithelial cells in both in vitro and in vivo studies. Delivery of MSCs was found to improve retinal morphology and function and delay retinal degeneration. In this review, we revisit the therapeutic role of MSCs in the diseased eye. Furthermore, we reveal the possible cellular mechanisms and identify the associated signaling pathways of MSCs in reversing the pathological conditions of various ocular disorders such as age-related macular degeneration (AMD), retinitis pigmentosa, diabetic retinopathy, and glaucoma. Current stem cell treatment can be dispensed as an independent cell treatment format or with the combination of other approaches. Hence, the improvement of the treatment strategy is largely subjected by our understanding of MSCs mechanism of action., Competing Interests: The authors declare no conflict of interest.

The article in the journal "Molecular Neurodegeneration" discusses the development of a novel AAV vector, AAV206, for gene therapy of RPE-related retinal degenerative diseases via intravitreal delivery. The study highlights the high specificity and efficiency of AAV206 in transducing RPE cells, with lower retinal toxicity and immunogenicity compared to conventional AAV2 vectors. Additionally, the research demonstrates that AAV206-sFLT shows superior efficacy in inhibiting CNV formation in a laser-induced CNV mouse model compared to AAV2-sFLT. The findings suggest that AAV206 holds promise as a valuable tool for treating RPE-related retinal degenerative diseases. [Extracted from the article]

The escalating prevalence of retinal diseases—notably, age-related macular degeneration and hereditary retinal disorders—poses an intimidating challenge to ophthalmic medicine, often culminating in irreversible vision loss. Current treatments are limited and often fail to address the underlying loss of retinal cells. This paper explores the potential of stem-cell-based therapies as a promising avenue for retinal regeneration. We review the latest advancements in stem cell technology, focusing on embryonic stem cells (ESCs), pluripotent stem cells (PSCs), and mesenchymal stem cells (MSCs), and their ability to differentiate into retinal cell types. We discuss the challenges in stem cell transplantation, such as immune rejection, integration into the host retina, and functional recovery. Previous and ongoing clinical trials are examined to highlight the therapeutic efficacy and safety of these novel treatments. Additionally, we address the ethical considerations and regulatory frameworks governing stem cell research. Our analysis suggests that while stem-cell-based therapies offer a groundbreaking approach to treating retinal diseases, further research is needed to ensure long-term safety and to optimize therapeutic outcomes. This review summarizes the clinical evidence of stem cell therapy and current limitations in utilizing stem cells for retinal degeneration, such as age-related macular degeneration, retinitis pigmentosa, and Stargardt's disease. [ABSTRACT FROM AUTHOR]

Retinal degenerative diseases, including diabetic retinopathy (DR) and age-related macular degeneration (AMD), loom as threats to vision, causing detrimental effects on the structure and function of the retina. Central to understanding these diseases, is the compromised state of the blood-retinal barrier (BRB), an effective barrier that regulates the influx of immune and inflammatory components. Whether BRB breakdown initiates retinal distress, or is a consequence of disease progression, remains enigmatic. Nevertheless, it is an indication of retinal dysfunction and potential vision loss. The intricate intercellular dialogues among retinal cell populations remain unintelligible in the complex retinal milieu, under conditions of inflammation and oxidative stress. The retina, a specialized neural tissue, sustains a ceaseless demand for oxygen and nutrients from two vascular networks. The BRB orchestrates the exchange of molecules and fluids within this specialized region, comprising the inner BRB (iBRB) and the outer BRB (oBRB). Extracellular vesicles (EVs) are small membranous structures, and act as messengers facilitating intercellular communication in this milieu. EVs, both from retinal and peripheral immune cells, increase complexity to BRB dysfunction in DR and AMD. Laden with bioactive cargoes, these EVs can modulate the retinal microenvironment, influencing disease progression. Our review delves into the multifaceted role of EVs in retinal degenerative diseases, elucidating the molecular crosstalk they orchestrate, and their microRNA (miRNA) content. By shedding light on these nanoscale messengers, from their biogenesis, release, to interaction and uptake by target cells, we aim to deepen the comprehension of BRB dysfunction and explore their therapeutic potential, therefore increasing our understanding of DR and AMD pathophysiology. [ABSTRACT FROM AUTHOR]

Kinases play crucial roles in the pathophysiology of retinal degenerative diseases. These diseases, such as diabetic retinopathy, age-related macular degeneration, glaucoma, and retinitis pigmentosa, are characterized by progressive degeneration of retinal cells, including photoreceptors, ganglion cells, vascular cells, and retinal pigment epithelium, among others. The involvement of kinases in cell survival and apoptosis, immune responses and inflammation regulation, mitochondrial functions and mitophagy, autophagy, and proteostasis is crucial for maintaining cellular homeostasis and responding to various stressors. This review highlights the importance of studying kinases to better understand their functions and, regulation permitting, enable the identification of novel molecular players or potential drug targets and, consequently, the development of more effective and precise treatments to slow or halt the progression of retinal degenerative diseases. [ABSTRACT FROM AUTHOR]

The main degenerative diseases of the retina include macular degeneration, proliferative vitreoretinopathy, retinitis pigmentosa, and glaucoma. Novel approaches for treating retinal diseases are based on cell replacement therapy using a variety of exogenous stem cells. An alternative and complementary approach is the potential use of retinal regeneration cell sources (RRCSs) containing retinal pigment epithelium, ciliary body, Müller glia, and retinal ciliary region. RRCSs in lower vertebrates in vivo and in mammals mostly in vitro are able to proliferate and exhibit gene expression and epigenetic characteristics typical for neural/retinal cell progenitors. Here, we review research on the factors controlling the RRCSs' properties, such as the cell microenvironment, growth factors, cytokines, hormones, etc., that determine the regenerative responses and alterations underlying the RRCS-associated pathologies. We also discuss how the current data on molecular features and regulatory mechanisms of RRCSs could be translated in retinal biomedicine with a special focus on (1) attempts to obtain retinal neurons de novo both in vivo and in vitro to replace damaged retinal cells; and (2) investigations of the key molecular networks stimulating regenerative responses and preventing RRCS-related pathologies. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase 3 (GSK3) is a key regulator of many cellular signaling processes and performs a wide range of biological functions in the nervous system. Due to its central role in numerous cellular processes involved in cell degeneration, a rising number of studies have highlighted the interest in developing therapeutics targeting GSK3 to treat neurodegenerative diseases. Although recent works strongly suggest that inhibiting GSK3 might also be a promising therapeutic approach for retinal degenerative diseases, its full potential is still under-evaluated. In this review, we summarize the literature on the role of GSK3 on the main cellular functions reported as deregulated during retinal degeneration, such as glucose homeostasis which is critical for photoreceptor survival, or oxidative stress, a major component of retinal degeneration. We also discuss the interest in targeting GSK3 for its beneficial effects on inflammation, for reducing neovascularization that occurs in some retinal dystrophies, or for cell-based therapy by enhancing Müller glia cell proliferation in diseased retina. Together, although GSK3 inhibitors hold promise as therapeutic agents, we highlight the complexity of targeting such a multitasked kinase and the need to increase our knowledge of the impact of reducing GSK3 activity on these multiple cellular pathways and biological processes. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this paper is to investigate how the imbalance of neurogenic factor (NGF) and its precursor (pro-NGF) mediates structural and functional impairment of retinal neurovascular unit (RNVU) that plays a role in retinal degenerative diseases. Methods: A literature search of electronic databases was performed. Results: The pro-apoptotic effect of pro-NGF and the pro-growth effect of NGF are essential for the pathological and physiological activities of RNVU. Studies show that NGF-based treatment of retinal degenerative diseases, including glaucoma, age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy, has achieved remarkable efficacy. Conclusions: RNVU plays a complex and multifaceted role in retinal degenerative diseases. The exploration of the differential signaling expression of proNGF-NGF homeostasis under physiological and pathological conditions, and the corresponding pathological processes induced by its regulation, has prompted us to focus on earlier retinal neuroprotective therapeutic strategies to prevent retinal degenerative diseases. [ABSTRACT FROM AUTHOR]

Retinal degenerative diseases are a leading cause of vision loss and blindness throughout the world, characterized by chronic and progressive loss of neurons and/or myelin. One of the common features of retinal degenerative diseases and central neurodegenerative diseases is chronic neuroinflammation. Interleukin-17A (IL-17A) is the cytokine most closely related to disease in its family. Accumulating evidence suggests that IL-17A plays a key role in human retinal degenerative diseases, including age-related macular degeneration, diabetic retinopathy and glaucoma. This review aims to provide an overview of the role of IL-17A participating in the pathogenesis of retinal degenerative diseases, which may open new avenues for potential therapeutic interventions. [ABSTRACT FROM AUTHOR]

Retinal degenerative diseases are a group of heterogeneous eye diseases that affect a significant percentage of the world's population, i.e., age-related macular degeneration (AMD), diabetic retinopathy, retinitis pigmentosa (RP), and glaucoma. Regenerative medicines look for novel therapies for severe injuries or chronic diseases, e.g., retina degeneration. Müller glia is the only retinal glia type with a common embryonic origin, with retinal neurons derived from the neural crest. Also, the lack of neurons in the retina does not automatically regenerate. Therefore, Müller glial cells, which make up about 5% of retinal cells, are a potent source for retinal regeneration. Following the retinal damage, Müller glial cells dedifferentiate and re-enter the cell cycle, producing multipotent progenitor cells. This feature leads to applying Müller glial cells in the regeneration of the retina. This study reviews this feature's molecular and clinical approaches, focusing on the critical signaling pathways, generation and transplantation methods, and clinical and sub-clinical challenges. [ABSTRACT FROM AUTHOR]

Retinal degenerative diseases (RDDs) are a group of diseases contributing to irreversible vision loss with yet limited therapies. Stem cell-based therapy is a promising novel therapeutic approach in RDD treatment. Mesenchymal stromal/stem cells (MSCs) have emerged as a leading cell source due to their neurotrophic and immunomodulatory capabilities, limited ethical concerns, and low risk of tumor formation. Several pre-clinical studies have shown that MSCs have the potential to delay retinal degeneration, and recent clinical trials have demonstrated promising safety profiles for the application of MSCs in retinal disease. However, some of the clinical-stage MSC therapies have been unable to meet primary efficacy end points, and severe side effects were reported in some retinal "stem cell" clinics. In this review, we provide an update of the interaction between MSCs and the RDD microenvironment and discuss how to balance the therapeutic potential and safety concerns of MSCs' ocular application. [ABSTRACT FROM AUTHOR]

The prevalence of retinal degenerative diseases, including age-related macular degeneration and retinitis pigmentosa, has been increasing globally and is linked to the aging population and improved life expectancy. These diseases are characterized by chronic, progressive neuronal damage or depletion of the photoreceptor cells in the retina, and limited effective treatment options are currently available. Mesenchymal stem cell-derived exosomes (MSC-EXOs) containing cytokines, growth factors, lipids, mRNA, and miRNA, which act as mediators of intercellular communication transferring bioactive molecules to recipient cells, offer an appealing, non-cellular nanotherapeutic approach for retinal degenerative diseases. However, treatment specificity is compromised due to their high heterogeneity in size, content, functional effects, and parental cellular source. To improve this, engineered MSC-EXOs with increased drug-loading capacity, targeting ability, and resistance to bodily degradation and elimination have been developed. This review summarizes the recent advances in miRNAs of MSC-EXOs as a treatment for retinal degeneration, discussing the strategies and methods for engineering therapeutic MSC-EXOs. Notably, to address the single functional role of engineered MSC-EXOs, we propose a novel concept called "Compound Engineered MSC-EXOs (Co-E-MSC-EXOs)" along with its derived potential therapeutic approaches. The advantages and challenges of employing Co-E-MSC-EXOs for retinal degeneration in clinical applications, as well as the strategies and issues related to them, are also highlighted. [Display omitted] • The novel notion of "Compound Engineered MSC-EXOs" is proposed. • Co-E-MSC-EXOs contain the principal, deputy, and auxiliary components. • Co-MSC-EXOs may pair with an anti-VEGF agent to suppress wet AMD. • The clinical application of Co-E-MSC-EXOs in retinal degeneration is discussed. • Standardizing the production, purification, and storage of Co-MSC-EXOs is required. [ABSTRACT FROM AUTHOR]

As the third gasotransmitter, hydrogen sulfide (H2S) plays a crucial role in the physiology and pathophysiology of many systems in the body, such as the nervous, cardiovascular, respiratory, and gastrointestinal systems. The mechanisms for its effects, including inhibiting ischemic injury, reducing oxidative stress damage, regulating apoptosis, and reducing the inflammation reaction in different systems, have not been fully understood. Recently, H2S and its endogenous synthesis pathway were found in the mammalian retina. This review describes the production and the metabolism of H2S and the evidence of a role of H2S in the retina physiology and in the different retinal diseases, including retinal degenerative diseases and vascular diseases. In the retina, H2S is generated in the presence of cystathionine-β-synthase, cystathionine-g-lyase, and 3-mercaptopyruvate sulfurtransferase from L-cysteine. The role of endogenous H2S and its physiologic effect in the retina are still elusive. However, strong evidence shows that retina-derived H2S might play protective or deleterious role in the pathogenesis of retinal diseases. For example, by regulating Ca2+ influx, H2S can protect retinal neurons against light-induced degeneration. H2S preconditioning can mediate the antiapoptotic effect of retinal ganglion cells in retinal ischemia/reperfusion injury. Treatment with H2S in rats relieves diabetic retinopathy by suppressing oxidative stress and reducing inflammation. Further studies would greatly improve our understanding of the pathophysiologic mechanisms responsible for retinal diseases and the potential for the H2S-related therapy of the retinal diseases as well. [ABSTRACT FROM AUTHOR]

Abstract: Recent studies have suggested a possible involvement of abnormal tau in some retinal degenerative diseases. The common view in these studies is that these retinal diseases share the mechanism of tau-mediated degenerative diseases in brain and that information about these brain diseases may be directly applied to explain these retinal diseases. Here we collectively examine this view by revealing three basic characteristics of tau in the rod outer segment (ROS) of bovine retinal photoreceptors, i.e., its isoforms, its phosphorylation mode and its interaction with microtubules, and by comparing them with those of brain tau. We find that ROS contains at least four isoforms: three are identical to those in brain and one is unique in ROS. All ROS isoforms, like brain isoforms, are modified with multiple phosphate molecules; however, ROS isoforms show their own specific phosphorylation pattern, and these phosphorylation patterns appear not to be identical to those of brain tau. Interestingly, some ROS isoforms, under the normal conditions, are phosphorylated at the sites identical to those in Alzheimer's patient isoforms. Surprisingly, a large portion of ROS isoforms tightly associates with a membranous component(s) other than microtubules, and this association is independent of their phosphorylation states. These observations strongly suggest that tau plays various roles in ROS and that some of these functions may not be comparable to those of brain tau. We believe that knowledge about tau in the entire retinal network and/or its individual cells are also essential for elucidation of tau-mediated retinal diseases, if any. [Copyright &y& Elsevier]

Dietary polyphenols are a group of natural compounds that have been proposed to have beneficial effects on human health. They were first known for their antioxidant properties, but several studies over the years have shown that these compounds can exert protective effects against chronic diseases. Nonetheless, the mechanisms underlying these potential benefits are still uncertain and contradictory effects have been reported. In this review, we analyze the potential effects of polyphenol compounds on some visual diseases, with a special focus on retinal degenerative diseases. Current effective therapies for the treatment of such retinal diseases are lacking and new strategies need to be developed. For this reason, there is currently a renewed interest in finding novel ligands (or known ligands with previously unexpected features) that could bind to retinal photoreceptors and modulate their molecular properties. Some polyphenols, especially flavonoids (e.g., quercetin and tannic acid), could attenuate light-induced receptor damage and promote visual health benefits. Recent evidence suggests that certain flavonoids could help stabilize the correctly folded conformation of the visual photoreceptor protein rhodopsin and offset the deleterious effect of retinitis pigmentosa mutations. In this regard, certain polyphenols, like the flavonoids mentioned before, have been shown to improve the stability, expression, regeneration and folding of rhodopsin mutants in experimental in vitro studies. Moreover, these compounds appear to improve the integration of the receptor into the cell membrane while acting against oxidative stress at the same time. We anticipate that polyphenol compounds can be used to target visual photoreceptor proteins, such as rhodopsin, in a way that has only been recently proposed and that these can be used in novel approaches for the treatment of retinal degenerative diseases like retinitis pigmentosa; however, studies in this field are limited and further research is needed in order to properly characterize the effects of these compounds on retinal degenerative diseases through the proposed mechanisms. [ABSTRACT FROM AUTHOR]

Retinal degenerative diseases, such as age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy or glaucoma, represent the main causes of a decreased quality of vision or even blindness worldwide. However, despite considerable efforts, the treatment possibilities for these disorders remain very limited. A perspective is offered by cell therapy using mesenchymal stem cells (MSCs). These cells can be obtained from the bone marrow or adipose tissue of a particular patient, expanded in vitro and used as the autologous cells. MSCs possess potent immunoregulatory properties and can inhibit a harmful inflammatory reaction in the diseased retina. By the production of numerous growth and neurotrophic factors, they support the survival and growth of retinal cells. In addition, MSCs can protect retinal cells by antiapoptotic properties and could contribute to the regeneration of the diseased retina by their ability to differentiate into various cell types, including the cells of the retina. All of these properties indicate the potential of MSCs for the therapy of diseased retinas. This view is supported by the recent results of numerous experimental studies in different preclinical models. Here we provide an overview of the therapeutic properties of MSCs, and their use in experimental models of retinal diseases and in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) cell transplants have served as a cell therapy for treating retinal degenerative diseases. However, how to optimize the survival and engraftment of hESC-RPE cells is a great challenge. Methods: Here, we report hESC-RPE cells that are embedded with polyelectrolytes gelatin and alginate by layer-by-layer (LbL) self-assembly technique, based on the opposite charge of alternate layers. Cells were assessed for cell survival, immunogenicity, and function in vitro and in vivo. Results: This strategy obviously decreased the immunogenicity of hESC-RPE cells without affecting its activity. LbL-RPE cell transplants into the subretinal space of Royal College of Surgeons (RCS) rats optimized cell engraftment and decreased immunogenicity compared to untreated RPE cell transplants (immunosuppression was not used during the 21-week study). Visual-functional assay with electroretinogram recordings (ERGs) also showed higher B wave amplitudes in RCS rats with LbL-RPE cell transplants. Conclusions: We demonstrate that transplanted LbL-RPE cells have better viability and grafting efficiency, optimized immunogenicity, and visual function. Therefore, LbL engineering is a promising method to increase the efficacy of hESC-RPE cell transplantation. [ABSTRACT FROM AUTHOR]