Human pluripotent stem cells for the modelling of diseases of the retina and optic nerve: toward a retina in a dish
Introduction
The eye is a complex structure composed of several layers of specialized tissues that together play a role in generating vision (Figure 1). Light enters the eye through the clear tissue at the front of the eye, the cornea, which refracts lights and enables the signal to pass through the pupil and through the lens, a structure that further focuses the light before it travels through the vitreous to the outermost cells of the retina to initiate the phototransduction cascade in photoreceptors, with stray light being absorbed by the retinal pigment epithelium (RPE) (Figure 1). A biochemical process known as the visual cycle ensues, involving the generation and recycling of photosensitive compounds leading to photoreceptor activation. The chemical and electrical signals generated by the photoreceptors are then transmitted through adjacent bipolar cells, which synapse onto the innermost retinal neurons, the retinal ganglion cells (RGCs) (Figure 1), carrying the action potential to the brain via the optic nerve for eventual processing in the visual cortex. Additional retinal neurons such as horizontal and amacrine cells transmit information laterally. In diseases affecting the retina (retinal dystrophies, retinal degenerations) and/or optic nerve (optic neuropathies), some molecular processes involved in the generation and processing of visual information become impaired, due to cell dysfunction or death. Retinal dystrophies and degenerations generally manifest through disruption of photoreceptor or RPE function and integrity, whilst optic neuropathies largely affect the RGCs. Nonetheless, other cell types can also be involved in these various diseases. For instance, Müller-glial cells, are central to the pathology of Macular Telangiectasia type 2 [1]. Further to this, many diseases involve multiple cell types and cellular interactions that are likely to be fundamental to normal function and pathogenesis. Modelling cellular interactions is difficult to assess in vivo and is not recapitulated in conventional cell cultures. Here we will review the current state of research in the modelling of the retina and optic nerve using human pluripotent stem cells (hPSCs) and derivatives.
Section snippets
Current models and their limitations
Although retinal and optic nerve diseases are generally well characterized clinically, the molecular events underlying pathologies often remain poorly understood. Age-related macular degeneration (AMD) exemplifies this problem: despite international efforts to understand its pathogenesis, there is still no effective treatment or cure for the non-exudative, (atrophic or dry) form of AMD. The early stages of AMD are characterized by the presence of extracellular deposits, known as drusen, that
Human pluripotent stem cells and disease modelling
hPSCs, including embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), are a powerful tool to investigate retinal and optic nerve diseases, as cells from selected individuals or specific genetic background can be differentiated into specific cell types of interest to obtain disease models for drug screening and therapy development [9••]. Those cells thus bring to the forefront of research the ability to generate ‘a biopsy in a dish’. This is particularly relevant for the
A retina in a dish: increasing disease modelling complexity
By utilizing iPSC-derived retinal cells, we have, in theory, the unprecedented potential to produce patient-specific human ‘retinas’ in vitro, enabling unrestricted access to the stratified cells that comprise the tissue as it exists in vivo. As such, microenvironmental factors of disease such as oxidation, stress response and inflammation could be mimicked in vitro, creating a disease model in a dish able to capture and trace the interdependent responses of retinal cells as they likely exist
Conclusion
Given that the retina is a symbiotic tissue, with various cell types operating interdependently to relay light to the brain, the accurate modelling of retinal and optic nerve diseases requires participation of multiple cell types to extrapolate pathogenesis. Currently, simple monolayer cultures fail to capture the complexity of retinal diseases, highlighting the need for more complex and accurate models. Development of such models will aid the preclinical validation and development of novel
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship (1154389, AP), grants from the Macular Disease Foundation of Australia, the Jack Brockhoff Foundation, the Therapeutics Technologies Research Initiative – University of Melbourne, Stem Cells Australia – the Australian Research Council (ARC) Special Research Initiative in Stem Cell Science and the ARC Training Centre for Personalised Therapeutics Technologies (IC170100016) and funded by
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2021, Genomics, Proteomics and BioinformaticsCitation Excerpt :A short-time differentiation (1 month) was chosen as it represents a time point routinely used in in vitro assays of RPE [3]. A prolonged time course of differentiation (12 months) was chosen as its characterization could be subsequently used for comparison with other retinal cell differentiation methods, in particular of retinal organoids and photoreceptors, for which differentiation and relative maturity are obtained after prolonged time in culture and would thus be present at that later time point [11–14]. The human embryonic stem cell (hESC) line H9 was differentiated to RPE cells following the protocol described in the Materials and methods section.
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