Abstract
Inherited retinal degenerations (IRD) affecting either photoreceptors or pigment epithelial cells cause progressive visual loss and severe disability, up to complete blindness. Retinal organoids (ROs) technologies opened up the development of human inducible pluripotent stem cells (hiPSC) for disease modeling and replacement therapies. However, hiPSC-derived ROs applications to IRD presently display limited maturation and functionality, with most photoreceptors lacking well-developed outer segments (OS) and light responsiveness comparable to their adult retinal counterparts. In this review, we address for the first time the microenvironment where OS mature, i.e., the subretinal space (SRS), and discuss SRS role in photoreceptors metabolic reprogramming required for OS generation. We also address bioengineering issues to improve culture systems proficiency to promote OS maturation in hiPSC-derived ROs. This issue is crucial, as satisfying the demanding metabolic needs of photoreceptors may unleash hiPSC-derived ROs full potential for disease modeling, drug development, and replacement therapies.
Highlights
The notion of immature photoreceptor precursors in human inducible pluripotent stem cells (hiPSC)-derived Retinal organoids (ROs) is consistent with the analysis of voltage- and cGMP-gated currents carried out at different developmental time of ROs generated with the same mixed 2D–3D protocol used to generate ROs with functional PRC [132]
Demonstrate the possibility of generating and isolating properly developed donor cells for transplantation. These impressive achievements represent an undeniable success that paves the way toward developing a cure for Inherited retinal degenerations (IRD) by replacing missing cells with iPSC-derived cells
In vitro modeling of IRD caused by defective genes coding for phototransduction components requires the well-developed outer segments (OS) to investigate the pathogenetic mechanisms associated with the misfolding of highly expressed proteins, such as rhodopsin, or the metabolic overload caused by variants affecting cGMP turnover
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Cyan arrows: downward transfer of rod-borne signals via primary and secondary rod depolarizing rod BC (blue). Horizontal cyan arrows indicate the transfer of rod-borne signals to pathways. Primary rod pathway: downward pointing cyan arrows indicate rod responses transfer cone BC by AII AC (orange), via a chemical synapsis with HCB and an electrical synapsis (red circle to depolarizing rod BC (blue). Horizontal cyan arrows indicate the transfer of rod-borne signals to containing a resistor symbol) with depolarizing CB. Secondary rod pathway: horizontal cyan arrows cone BC by AII AC (orange), via a chemical synapsis with HCB and an electrical synapsis Secondary rod pathway: horizontal cyan arrows indicate the transfer of rod-borne signals to cones via electrical synapses.
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