Differentiation Of Retinal Stem Cells Research Articles

Epigenetics and Degenerative Retinal Diseases: Prospects for New Therapeutic Approaches.

There is growing evidence that retinal degenerative diseases are accompanied by epigenetic changes in both deoxyribonucleic acid methylation and histone modification. Even in the monogenic disease retinitis pigmentosa, there is a cascade of changes in gene expression that correlate with epigenetic changes, suggesting that many of the symptoms, and degenerative changes, may be a result of epigenetic changes downstream from the genetic mutation. This is supported by data from studies of diabetic retinopathy and macular degeneration, 2 diseases where it has been difficult to define a single causative change. Initial studies with modifiers of deoxyribonucleic acid methylation suggest that they can provide therapeutic benefit. A number of drugs are available to inhibit specific epigenetic histone modifier enzymes, and these offer the possibility of new therapeutic approaches to retinal disease. Systemic treatment with inhibitors of histone demethylases and histone deacetylases have arrested rod degeneration in rodent models of retinitis pigmentosa. Some evidence has suggested that similar treatments may provide benefits for patients with diabetic retinopathy. Because differentiation of retinal stem cells is regulated in part by epigenetic mechanisms, it may also be possible to direct stem cell differentiation pathways through the use of selective epigenetic modifiers. This is predicted to provide a valuable avenue to accelerate the introduction of regenerative approaches to retinal disease. Epigenetic modifiers are poised to become a powerful new approach to treat retinal degenerative diseases.

Combined pulses of light and sound in the retina with nutraceuticals may enhance the recovery of foveal holes.

The present manuscript stems from evidence, which indicates that specific wavelength produce an activation of the autophagy pathway in the retina. These effects were recently reported to synergize with the autophagy-inducing properties of specific phytochemicals. The combined administration of photo-modulation and phytochemicals was recently shown to have a strong potential in eliciting the recovery in the course of retinal degeneration and it was suggested as a non-invasive approach named "Lugano protocol" to treat age-related macular degeneration (AMD). Recent translational findings indicate that the protective role of autophagy may extend also to acute neuronal injuries including traumatic neuronal damage. At the same time, very recent investigations indicate that autophagy activation and retinal anatomical recovery may benefit from sound exposure. Therefore, in the present study, the anatomical rescue of a traumatic neuronal loss at macular level was investigated in a patient with idiopathic macular hole by using a combined approach of physical and chemical non-invasive treatments. In detail, light exposure was administered in combination with sound pulses to the affected retina. This treatment was supplemented by phytochemicals known to act as autophagy inducers, which were administered orally for 6 months. This combined administration of light and sound with nutraceuticals reported here as Advanced Lugano's Protocol (ALP) produced a remarkable effect in the anatomical architecture of the retina affected by the macular hole. The anatomical recovery was almost complete at roughly one year after diagnosis and beginning of treatment. The structural healing of the macular hole was concomitant with a strong improvement of visual acuity and the disappearance of metamorphopsia. The present findings are discussed in the light of a synergism shown at neuronal level between light and sound in the presence of phytochemicals to stimulate autophagy and promote proliferation and neuronal differentiation of retinal stem cells.

Bone marrow mesenchymal stem cells modified by angiogenin‐1 promotes tissue repair in mice with oxygen‐induced retinopathy of prematurity by promoting retinal stem cell proliferation and differentiation

Retinopathy has become one of the major factors that lead to blindness worldwide. Although many clinical therapies are concerned about such disease, most of them focus on symptoms alleviation. In this study, we aim to investigate whether coculture retinal stem cells (RSCs) with bone marrow mesenchymal stem cells transfected with angiogenin-1 (Ang-1-BMSCs) affects the damaged retinal tissue of oxygen-induced retinopathy of prematurity (OIR-ROP) mice. After OIR-ROP mouse model establishment, Ang-1-BMSCs, RSCs, and OIR-ROP retinal tissues were cocultured in a a transwell chamber. RSCs proliferation and the expression of Ang-1, insulin-like growth factor-1 (IGF-1) in the supernatant of RSCs, as well as β-tubulin and protein kinase C (PKC) expression were evaluated. Finally, the repair of OIR-ROP mice retinal tissues was observed by injecting Ang-1-BMSCs + RSCs. In the OIR-ROP mouse model, RSCs cocultured with OIR-ROP retinal tissues could be induced to differentiate into cells expressing β-tubulin and PKC and promote the expression of Ang-1 and IGF-1. coculture of Ang-1-BMSCs further enhanced the proliferation and differentiation of RSCs by promoting the expression of Ang-1 and IGF-1. Coculture of RSCs + Ang-1-BMSCs induced differentiation of Ang-1-BMSCs through interaction among intercellular factors and restored the damaged retinal tissue of OIR-ROP mice. Collectively, our study provided evidence that coculture of Ang-1-BMSCs and RSCs could promote the proliferation and differentiation of RSCs and improve the treatment for the damaged retina tissue of OIR-ROP mice.

Growth/differentiation 5 promotes the differentiation of retinal stem cells into neurons via Atoh8.

Retinal diseases are characterized by the degeneration of retinal neural cells, and are the main cause of blindness. Although the development of stem cell including retinal stem cell therapies raises hope for retinal neuron replacement, currently, there is still no efficient method to regenerate retinal neurons. To realize the potential roles of the production of retinal neurons, neurotrophic factor direct the differentiation of retinal stem cells should be extensively identified. In this article, we characterized growth/differentiation 5 (GDF5), which caused the activation of Smad signaling, can induce neurogenesis and neurite outgrowth in retinal stem cell differentiation. Moreover, a bHLH transcription factor, Atoh8 modulates the effects stimulated by GDF5. These data suggested that GDF5 regulates neuron differentiation through mediating Atoh8 and help us to understand the pathophysiological function of GDF5 in retinal regeneration.

Neuronal differentiation in the early human retinogenesis

AimOur study investigates the differentiation of retinal stem cells towards different neuronal subtypes during the critical period of human eye development. MethodsExpression of the neuronal marker neurofilament 200 (NF200), tyrosine hydroxilase (TH) and choline acetyltransferase (ChAT) was seen by immunofluorescence in the 5th–12th – week stage of development in the human eye. Data was analysed by Mann–Whitney, Kruskal–Wallis and Dunn’s post hoc tests. ResultsNF200, TH and ChAT cells appeared in the 5th/6th week and gradually increased during further development. The proportion of TH positive areas were distributed similarly to NF200, with a higher proportion in the outer neuroblastic layer. The proportion of a ChAT positive surface was highest in the 5th/6th – week whilst from the 7th week onwards, its proportion became higher in the optic nerve and inner neuroblastic layers than in the outer layer, where a decrease of ChAT positive areas were seen. ConclusionsOur study indicates a high differentiation potential of early retinal cells, which decreased with the advancement of development. The observed great variety of retinal phenotypic expressions results from a large scale of influences, taking place at different developmental stages.

Stem cells as source for retinal pigment epithelium transplantation.

Inherited maculopathies, age related macular degeneration and some forms of retinitis pigmentosa are associated with impaired function or loss of the retinal pigment epithelium (RPE). Among potential treatments, transplantation approaches are particularly promising. The arrangement of RPE cells in a well-defined tissue layer makes the RPE amenable to cell or tissue sheet transplantation. Different cell sources have been suggested for RPE transplantation but the development of a clinical protocol faces several obstacles. The source should provide a sufficient number of cells to at least recover the macula area. Secondly, cells should be plastic enough to be able to integrate in the host tissue. Tissue sheets should be considered as well, but the substrate on which RPE cells are cultured needs to be carefully evaluated. Immunogenicity can also be an obstacle for effective transplantation as well as tumorigenicity of not fully differentiated cells. Finally, ethical concerns may represent drawbacks when embryo-derived cells are proposed for RPE transplantation. Here we discuss different cell sources that became available in recent years and their different properties. We also present data on a new source of human RPE. We provide a protocol for RPE differentiation of retinal stem cells derived from adult ciliary bodies of post-mortem donors. We show molecular characterization of the invitro differentiated RPE tissue and demonstrate its functionality based on a phagocytosis assay. This new source may provide tissue for allogenic transplantation based on best matches through histocompatibility testing.

Atoh7 promotes the differentiation of retinal stem cells derived from Müller cells into retinal ganglion cells by inhibiting Notch signaling

IntroductionRetinal Müller cells exhibit the characteristics of retinal progenitor cells, and differentiate into ganglion cells under certain conditions. However, the number of ganglion cells differentiated from retinal Müller cells falls far short of therapeutic needs. This study aimed to develop a novel protocol to promote the differentiation of retinal Müller cells into ganglion cells and explore the underlying signaling mechanisms.MethodsMüller cells were isolated and purified from rat retina and induced to dedifferentiate into retinal stem cells. Next the stem cells were transfected with lentivirus PGC-FU-GFP or lentivirus PGC-FU-Atoh7-GFP. In addition, the stem cells were transfected with Brn-3b siRNA or Isl-1 siRNA or treated with Notch inhibitor gamma-secretase inhibitor (GSI).ResultsThe proportion of ganglion cells differentiated from Atoh7-tranfected stem cells was significantly higher than that of controls. Knockdown of Brn-3b or Isl-1 inhibited, while GSI promoted, the differentiation into retinal ganglion cells. Atoh7 promoted the expression of Brn-3b and Isl-1 but inhibited the expression of Notch1.ConclusionsAtoh7 promotes the differentiation of Müller cells-derived retinal stem cells into retinal ganglion cells by inhibiting Notch signaling, thus opening up a new avenue for gene therapy and optic nerve regeneration in glaucoma.

Wnt signaling controls proliferation and differentiation of retinal stem cells in zebrafish

Wnt signaling controls proliferation and differentiation of retinal stem cells in zebrafish