Yuliya V. Markitantova

The retinal pigment epithelium (RPE) is a cellular source of retinal regeneration in lower vertebrates and a cellular source of retinal diseases in mammals, including humans. Both processes are based on a genetic program for the conversion of RPE cells into cells of other phenotypes: neural in the first case and mesenchymal in the second. RPE reprogramming in the neural direction is realized in tailed amphibians and bird embryos in vivo, but in higher vertebrates and humans, this process is realized in vitro. Epigenetic regulation determines the phenotypic plasticity of RPE cells, i.e., their choice of the cell differentiation pathway in animals of different classes. It has been suggested that the implementation of the genetic program for RPE reprogramming into different types of retinal neurons in adult amphibians and birds at the early stages of embryogenesis is conditioned by the specificity of the epigenetic landscape. The retinal RPE-dependent pathologies in mammals are characterized by different epigenetic signatures, and have a shared characteristic: specifically, a deficient epigenetic landscape (dysregulations in DNA methylation and histone modifications). Knowledge of the patterns and features of the epigenetic regulation of RPE cell behavior will allow us to obtain RPE cells that are in demand in medicine, from direct reprogramming with the possibility of epigenetically maintaining the cellular identities to the creation of neuro-regenerative technologies for the replacement therapy of RPE-dependent retinal pathologies in humans.

The structural and functional integrity of the retinal pigment epithelium (RPE) plays a key role in the normal functioning of the visual system. RPE cells are characterized by an efficient system of photoreceptor outer segment phagocytosis, high metabolic activity, and risk of oxidative damage. RPE dysfunction is a common pathological feature in various retinal diseases. Dysregulation of RPE cell proteostasis and redox homeostasis is accompanied by increased reactive oxygen species generation during the impairment of phagocytosis, lysosomal and mitochondrial failure, and an accumulation of waste lipidic and protein aggregates. They are the inducers of RPE dysfunction and can trigger specific pathways of cell death. Autophagy serves as important mechanism in the endogenous defense system, controlling RPE homeostasis and survival under normal conditions and cellular responses under stress conditions through the degradation of intracellular components. Impairment of the autophagy process itself can result in cell death. In this review, we summarize the classical types of oxidative stress-induced autophagy in the RPE with an emphasis on autophagy mediated by molecular chaperones. Heat shock proteins, which represent hubs connecting the life supporting pathways of RPE cells, play a special role in these mechanisms. Regulation of oxidative stress-counteracting autophagy is an essential strategy for protecting the RPE against pathological damage when preventing retinal degenerative disease progression.

Urodelean amphibians can regenerate the tail and the spinal cord (SC) and maintain this ability throughout their life. This clearly distinguishes these animals from mammals. The phenomenon of tail and SC regeneration is based on the capability of cells involved in regeneration to dedifferentiate, enter the cell cycle, and change their (or return to the pre-existing) phenotype during de novo organ formation. The second critical aspect of the successful tail and SC regeneration is the mutual molecular regulation by tissues, of which the SC and the apical wound epidermis are the leaders. Molecular regulatory systems include signaling pathways components, inflammatory factors, ECM molecules, ROS, hormones, neurotransmitters, HSPs, transcriptional and epigenetic factors, etc. The control, carried out by regulatory networks on the feedback principle, recruits the mechanisms used in embryogenesis and accompanies all stages of organ regeneration, from the moment of damage to the completion of morphogenesis and patterning of all its structures. The late regeneration stages and the effects of external factors on them have been poorly studied. A new model for addressing this issue is herein proposed. The data summarized in the review contribute to understanding a wide range of fundamentally important issues in the regenerative biology of tissues and organs in vertebrates including humans.

Retinal pigment epithelium (RPE) cells are important fundamentally for the development and function of the retina. In this regard, the study of the morphological and molecular properties of RPE cells, as well as their regenerative capabilities, is of particular importance for biomedicine. However, these studies are complicated by the fact that, despite the external morphological similarity of RPE cells, the RPE is a population of heterogeneous cells, the molecular genetic properties of which have begun to be revealed by sequencing methods only in recent years. This review carries out an analysis of the data from morphological and molecular genetic studies of the heterogeneity of RPE cells in mammals and humans, which reveals the individual differences in the subpopulations of RPE cells and the possible specificity of their functions. Particular attention is paid to discussing the properties of “stemness,” proliferation, and plasticity in the RPE, which may be useful for uncovering the mechanisms of retinal diseases associated with pathologies of the RPE and finding new ways of treating them.

The reprogramming of retinal pigment epithelium (RPE) cells into retinal cells (transdifferentiation) lies in the bases of retinal regeneration in several Urodela. The identification of the key genes involved in this process helps with looking for approaches to the prevention and treatment of RPE-related degenerative diseases of the human retina. The purpose of our study was to examine the transcriptome changes at initial stages of RPE cell reprogramming in adult newt Pleurodeles waltl. RPE was isolated from the eye samples of day 0, 4, and 7 after experimental surgical detachment of the neural retina and was used for a de novo transcriptome assembly through the RNA-Seq method. A total of 1019 transcripts corresponding to the differently expressed genes have been revealed in silico: the 83 increased the expression at an early stage, and 168 increased the expression at a late stage of RPE reprogramming. We have identified up-regulation of classical early response genes, chaperones and co-chaperones, genes involved in the regulation of protein biosynthesis, suppressors of oncogenes, and EMT-related genes. We revealed the growth in the proportion of down-regulated ribosomal and translation-associated genes. Our findings contribute to revealing the molecular mechanism of RPE reprogramming in Urodela.

Understanding the mechanisms triggering the initiation of retinal regeneration in amphibians may advance the quest for prevention and treatment options for degenerating human retina diseases. Natural retinal regeneration in amphibians requires two cell sources, namely retinal pigment epithelium (RPE) and ciliary marginal zone. The disruption of RPE interaction with photoreceptors through surgery or injury triggers local and systemic responses for retinal protection. In mammals, disease-induced damage to the retina results in the shutdown of the function, cellular or oxidative stress, pronounced immune response, cell death and retinal degeneration. In contrast to retinal pathology in mammals, regenerative responses in amphibians have taxon-specific features ensuring efficient regeneration. These include rapid hemostasis, the recruitment of cells and factors of endogenous defense systems, activities of the immature immune system, high cell viability, and the efficiency of the extracellular matrix, cytoskeleton, and cell surface remodeling. These reactions are controlled by specific signaling pathways, transcription factors, and the epigenome, which are insufficiently studied. This review provides a summary of the mechanisms initiating retinal regeneration in amphibians and reveals its features collectively directed at recruiting universal responses to trauma to activate the cell sources of retinal regeneration. This study of the integrated molecular network of these processes is a prospect for future research in demand biomedicine.

The retinal pigment epithelium (RPE) performs a range of necessary functions within the neural layers of the retina and helps ensure vision. The regulation of pro-oxidative and antioxidant processes is the basis for maintaining RPE homeostasis and preventing retinal degenerative processes. Long-term stable changes in the redox balance under the influence of endogenous or exogenous factors can lead to oxidative stress (OS) and the development of a number of retinal pathologies associated with RPE dysfunction, and can eventually lead to vision loss. Reparative autophagy, ubiquitin–proteasome utilization, the repair of damaged proteins, and the maintenance of their conformational structure are important interrelated mechanisms of the endogenous defense system that protects against oxidative damage. Antioxidant protection of RPE cells is realized as a result of the activity of specific transcription factors, a large group of enzymes, chaperone proteins, etc., which form many signaling pathways in the RPE and the retina. Here, we discuss the role of the key components of the antioxidant defense system (ADS) in the cellular response of the RPE against OS. Understanding the role and interactions of OS mediators and the components of the ADS contributes to the formation of ideas about the subtle mechanisms in the regulation of RPE cellular functions and prospects for experimental approaches to restore RPE functions.

During evolution and adaptation to life conditions, organisms have developed the strategies allowing them to use reactive oxygen species (ROS) in the regulation of physiological processes and maintenance of homeostasis. The retinal pigment epithelium (RPE) is one of the striking examples of tissues having a high metabolic rate and increased intracellular ROS production, and thus more liable to damage induced by exogenous or endogenous oxidative stress (OS) factors. Vertebrate RPE cells, despite the conservatism of eye tissues and their main functions, respond differently to OS because of the species specificity of signaling pathways components that make up the antioxidant defense system (AODS). Transcription factors (specifically, Nrf2) play a key role in the AODS. In the RPE, the latter includes several levels of regulation, whose interaction ensures the stability of the cellular morphofunctional state. Phylogenetic analysis of the key AODS components in various vertebrates revealed not only a conservatism, but also a variability in the protein domain organization, which may reflect the differences in functions, adaptability and regenerative potential of RPE cells. The identification of AODS-related mechanisms providing the morphofunctional stability of RPE cells is of fundamental importance for the search of tissue-specific targets facilitating effective treatment of various eye diseases.

The purinergic signaling system (PSS) occupies an exceptional position in the regulation of cellular processes, maintaining the homeostasis of the retina of vertebrates. In addition to general regularities, taxon-specific differences, genetically and metabolically determined, are manifested in the functioning of PSS in the retina. Signal cascades with the participation of PSS components can perform a dual role in the retina: they have both a damaging and protective effect, which is largely determined by the conditions of the cellular microenvironment and the molecular context. The identification of key components in the functioning of the PSS, linking it with other endogenous regulatory systems, creates prerequisites for the selection of cellular and molecular targets for neuroprotection in human retinal pathologies.

Retinal pigment epithelium (RPE) is a source of cells for retinal regeneration in amphibians in vivo and the development of retinal diseases in mammals and humans. Transdifferentiation of RPE cells into cells of other phenotypes is the basis for both processes: RPE cells transform into neural in the first case and into mesenchymal cells in the second case. The review describes the main stages of RPE cell transdifferentiation: initiation of the process, cell migration and proliferation, dedifferentiation, reprogramming, and specialization of cells into new directions. Information about the molecular and genetic mechanisms that ensure the passage of these stages by cells is given. Molecular participants of the regulation of transdifferentiation on the levels of the whole organism, the local cellular microenvironment (growth factors, signaling cascades), the expression of transcription factors, and the epigenome regulation are presented. Similarities and differences in the molecular and genetic mechanisms of implementation of different strategies for RPE transdifferentiation in amphibians and mammals are noted. The discovery of key molecular regulators of this choice serves both for the development of the theory of cellular reprogramming and approaches for the treatment of proliferative diseases of the human retina associated with RPE pathologies.