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Lookup NU author(s): Dr Maria Georgiou, Alex Chaudhary, Dr Joseph Collin, Dr Rachel Queen, Dr Birthe HilgenORCiD, Tracey DaveyORCiD, Professor David SteelORCiD, Professor Evelyne SernagorORCiD, Professor Lyle Armstrong, Professor Majlinda LakoORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Retinal drug toxicity screening is essential for the development of safe treatment strategies for a large number of diseases. To this end, retinal organoids derived from human pluripotent stem cells (hPSCs) provide a suitable screening platform due to their similarity to human retina and the ease of generation in large-scale formats. In this study, two hPSC cell lines were differentiated to retinal organoids, which comprised all key retinal cell types in multiple nuclear and synaptic layers. Single cell RNA-Seq of retinal organoids at day 200 of differentiation indicated the maintenance of retinal ganglion cells and development of bipolar cells: both cell types segregated into several subtypes. Ketorolac, Digoxin, Thioridazine, Sildenafil, Ethanol and Methanol were selected as key compounds to screen on retinal organoids because of their well-known retinal toxicity profile described in the literature. Exposure of the hPSC-derived retinal organoids to Digoxin, Thioridazine and Sildenafil exposure resulted in photoreceptor cell death, while Digoxin and Thioridazine additionally affected all other cell types, including Müller glia cells. All drug treatments caused activation of astrocytes, indicated by dendrites sprouting into neuroepithelium. The ability to respond to light was preserved in organoids although the number of responsive retinal ganglion cells decreased after drug exposure. These data indicate similar drug effects in organoids to those reported in in vivo models and/or in humans, thus providing the first robust experimental evidence of their suitability for toxicological studies.
Author(s): Dorgau B, Georgiou M, Chaudhary A, Molina M, Collin J, Queen R, Hilgen G, Davey T, Hewitt P, Schmitt M, Kustermann S, Pognan F, Steel D, Sernagor E, Armstrong L, Lako M
Publication type: Article
Publication status: Published
Journal: Stem Cell Translational Medicine
Year: 2022
Volume: 11
Issue: 2
Pages: 159-177
Online publication date: 19/02/2022
Acceptance date: 13/10/2021
Date deposited: 22/04/2022
ISSN (print): 2157-6564
ISSN (electronic): 2157-6580
Publisher: AlphaMed Press, Inc.
URL: https://doi.org/10.1093/stcltm/szab010
DOI: 10.1093/stcltm/szab010
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