Many forms of blindness result from the dysfunction or loss of retinal photoreceptors. Induced pluripotent stem cells (iPSCs) hold great potential for the modelling of these diseases or as potential ...therapeutic agents. However, to fulfill this promise, a remaining challenge is to induce human iPSC to recreate in vitro key structural and functional features of the native retina, in particular the presence of photoreceptors with outer-segment discs and light sensitivity. Here we report that hiPSC can, in a highly autonomous manner, recapitulate spatiotemporally each of the main steps of retinal development observed in vivo and form three-dimensional retinal cups that contain all major retinal cell types arranged in their proper layers. Moreover, the photoreceptors in our hiPSC-derived retinal tissue achieve advanced maturation, showing the beginning of outer-segment disc formation and photosensitivity. This success brings us one step closer to the anticipated use of hiPSC for disease modelling and open possibilities for future therapies.
The advent of stem cell-derived retinal organoids has brought forth unprecedented opportunities for developmental and physiological studies, while presenting new therapeutic promise for retinal ...degenerative diseases. From a translational perspective, organoid systems provide exciting new prospects for drug discovery, offering the possibility to perform compound screening in a three-dimensional (3D) human tissue context that resembles the native histoarchitecture and to some extent recapitulates cellular interactions. However, inherent variability issues and a general lack of robust quantitative technologies for analyzing organoids on a large scale pose severe limitations for their use in translational applications. To address this need, we have developed a screening platform that enables accurate quantification of fluorescent reporters in complex human iPSC-derived retinal organoids. This platform incorporates a fluorescence microplate reader that allows
-dimensional detection and fine-tuned wavelength selection. We have established optimal parameters for fluorescent reporter signal detection, devised methods to compensate for organoid size variability, evaluated performance and sensitivity parameters, and validated this technology for functional applications.
Retinal disease represents a growing global problem, both in terms of quality of life and economic impact, yet new therapies are not being developed at a sufficient rate to meet this mounting need. ...In this context, retinal organoids derived from human induced pluripotent stem cells hold significant promise for improving upon the current drug development process, increasing the speed and efficiency of moving potential therapeutic agents from bench to bedside. These organoid systems display the cell-cell and cell-matrix interactions, cellular heterogeneity, and physiological responses reflective of human biology and, thus, have the ability to replicate retinal disease pathology in a way that 2-dimensional cell cultures and animal models have been heretofore unable to achieve. However, organoid technology is not yet mature enough to meet the high-throughput demands of the first stages of drug screening. Hence, the augmentation of the existing drug development pipeline with retinal organoids, rather than the replacement of existing pathway components, may provide a way to harness the benefits of this improved pathological modeling. In this study, we outline the possible benefits of such a symbiosis, discuss other potential uses, and highlight barriers that remain to be overcome.
The ability to generate human retinas in vitro from pluripotent stem cells opened unprecedented opportunities for basic science and for the development of therapeutic approaches for retinal ...degenerative diseases. Retinal organoid models not only mimic the histoarchitecture and cellular composition of the native retina, but they can achieve a remarkable level of maturation that allows them to respond to light stimulation. However, studies evaluating the nature, magnitude, and properties of light-evoked responsivity from each cell type, in each retinal organoid layer, have been sparse. In this review we discuss the current understanding of retinal organoid function, the technologies used for functional assessment in human retinal organoids, and the challenges and opportunities that lie ahead.
The cumulative knowledge of retina development has been instrumental in the generation of retinal organoid systems from pluripotent stem cells; and these three-dimensional organoid models, in turn, ...have provided unprecedented opportunities for retinal research and translational applications, including the ability to model disease in a human setting and to apply these models to the development and validation of therapeutic drugs. In this review article, we examine how retinal organoids can also contribute to our understanding of retinal developmental mechanisms, how this knowledge can be applied to modeling developmental abnormalities, and highlight some of the avenues that remain to be explored.
Stem cells offer unprecedented opportunities for the development of strategies geared toward the treatment of retinal degenerative diseases. A variety of cellular sources have been investigated for ...various potential clinical applications, including tissue regeneration, disease modeling, and screening for non-cell-based therapeutic agents. As the field transitions from more than a decade of preclinical research to the first phase I/II clinical trials, we provide a concise overview of the stem cell sources most commonly used, weighing their therapeutic potential on the basis of their technical strengths/limitations, their ethical implications, and the extent of the progress achieved to date. This article serves as a framework for further in-depth analyses presented in the following chapters of this Special Issue.
Abstract
The chemical senses of taste and smell play a vital role in conveying information about ourselves and our environment. Tastes and smells can warn against danger and also contribute to the ...daily enjoyment of food, friends and family, and our surroundings. Over 12% of the US population is estimated to experience taste and smell (chemosensory) dysfunction. Yet, despite this high prevalence, long-term, effective treatments for these disorders have been largely elusive. Clinical successes in other sensory systems, including hearing and vision, have led to new hope for developments in the treatment of chemosensory disorders. To accelerate cures, we convened the “Identifying Treatments for Taste and Smell Disorders” conference, bringing together basic and translational sensory scientists, health care professionals, and patients to identify gaps in our current understanding of chemosensory dysfunction and next steps in a broad-based research strategy. Their suggestions for high-yield next steps were focused in 3 areas: increasing awareness and research capacity (e.g., patient advocacy), developing and enhancing clinical measures of taste and smell, and supporting new avenues of research into cellular and therapeutic approaches (e.g., developing human chemosensory cell lines, stem cells, and gene therapy approaches). These long-term strategies led to specific suggestions for immediate research priorities that focus on expanding our understanding of specific responses of chemosensory cells and developing valuable assays to identify and document cell development, regeneration, and function. Addressing these high-priority areas should accelerate the development of novel and effective treatments for taste and smell disorders.
The embryonic chick occupies a privileged place among animal models used in developmental studies. Its rapid development and accessibility for visualization and experimental manipulation are just ...some of the characteristics that have made it a vertebrate model of choice for more than two millennia. Until a few years ago, the inability to perform genetic manipulations constituted a major drawback of this system. However, the completion of the chicken genome project and the development of techniques to manipulate gene expression have allowed this classic animal model to enter the molecular age. Such techniques, combined with the embryological manipulations that this system is well known for, provide a unique toolkit to study the genetic basis of neural development. A major advantage of these approaches is that they permit targeted gene misexpression with extremely high spatiotemporal resolution and over a large range of developmental stages, allowing functional analysis at a level, speed and ease that is difficult to achieve in other systems. This article provides a general overview of the chick as a developmental model focusing more specifically on its application to the study of eye development. Special emphasis is given to the state of the art of the techniques that have made gene gain- and loss-of-function studies in this model a reality. In addition, we discuss some methodological considerations derived from our own experience that we believe will be beneficial to researchers working with this system.
Lens regeneration: a historical perspective Vergara, M Natalia; Tsissios, George; Del Rio-Tsonis, Katia
The International journal of developmental biology,
2018, Volume:
62, Issue:
6-7-8
Journal Article
Peer reviewed
Open access
The idea of regenerating injured body parts has captivated human imagination for centuries, and the topic still remains an area of extensive scientific research. This review focuses on the process of ...lens regeneration: its history, our current knowledge, and the questions that remain unanswered. By highlighting some of the milestones that have shaped our understanding of this phenomenon and the contributions of scientists who have dedicated their lives to investigating these questions, we explore how regeneration enquiry evolved into the science it is today, and how technological advances accelerated our understanding of these remarkable processes.
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