TY - JOUR
T1 - Human Retinal Organoids Provide a Suitable Tool for Toxicological Investigations
T2 - a Comprehensive Validation Using Drugs and Compounds Affecting the Retina
AU - Dorgau, Birthe
AU - Georgiou, Maria
AU - Chaudhary, Alexander
AU - Moya-Molina, Marina
AU - Collin, Joseph
AU - Queen, Rachel
AU - Hilgen, Gerrit
AU - Davey, Tracey
AU - Hewitt, Philip
AU - Schmitt, Michael
AU - Kustermann, Stefan
AU - Pognan, Francois
AU - Steel, David H.
AU - Sernagor, Evelyne
AU - Armstrong, Lyle
AU - Lako, Majlinda
N1 - Funding information: The authors are grateful for financial support from NC3Rs CRACKIT23 challenge (NC/CO16206/1). The authors would like to acknowledge the Bioimaging Unit (Newcastle University) for their support and assistance in this work.
PY - 2022/3/17
Y1 - 2022/3/17
N2 - 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 the 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 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 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.
AB - 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 the 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 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 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.
KW - human embryonic stem cells
KW - human induced pluripotent stem cells
KW - retina
KW - toxicology
KW - retinal organoids
KW - drug screening
UR - http://www.scopus.com/inward/record.url?scp=85126702253&partnerID=8YFLogxK
U2 - 10.1093/stcltm/szab010
DO - 10.1093/stcltm/szab010
M3 - Article
C2 - 35298655
SN - 2157-6564
VL - 11
SP - 159
EP - 177
JO - Stem cells translational medicine
JF - Stem cells translational medicine
IS - 2
ER -