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Updated: Jul 29, 2025
Toxicity Screens in Human Retinal Organoids for Pharmaceutical Discovery
Published on: March 4, 2021
Modeling inducible neuropathologies of the retina with differential phenotypes in organoids
Manuela Völkner1,2, Felix Wagner1,2, Thomas Kurth3
1Technische Universität Dresden, Center for Regenerative Therapies Dresden (CRTD), Dresden, Germany.
Abstract:
Neurodegenerative diseases remain incompletely understood and therapies are needed. Stem cell-derived organoid models facilitate fundamental and translational medicine research. However, to which extent differential neuronal and glial pathologic processes can be reproduced in current systems is still unclear. Here, we tested 16 different chemical, physical, and cell functional manipulations in mouse retina organoids to further explore this. Some of the treatments induce differential phenotypes, indicating that organoids are competent to reproduce distinct pathologic processes. Notably, mouse retina organoids even reproduce a complex pathology phenotype with combined photoreceptor neurodegeneration and glial pathologies upon combined (not single) application of HBEGF and TNF, two factors previously associated with neurodegenerative diseases. Pharmacological inhibitors for MAPK signaling completely prevent photoreceptor and glial pathologies, while inhibitors for Rho/ROCK, NFkB, and CDK4 differentially affect them. In conclusion, mouse retina organoids facilitate reproduction of distinct and complex pathologies, mechanistic access, insights for further organoid optimization, and modeling of differential phenotypes for future applications in fundamental and translational medicine research.
Insights
Mouse retina organoids can model complex neurodegenerative disease pathways, including photoreceptor and glial cell damage. This research offers new insights into disease mechanisms and therapeutic development for neurodegenerative conditions.
Area of Science:
- Neuroscience
- Stem Cell Biology
- Pathology
Background:
- Neurodegenerative diseases are poorly understood, highlighting the need for effective therapies.
- Stem cell-derived organoids offer promising models for both fundamental and translational research.
- The capacity of current organoid systems to replicate distinct neuronal and glial pathologies remains unclear.
Purpose of the Study:
- To investigate the extent to which mouse retina organoids can reproduce differential neuronal and glial pathological processes.
- To explore the utility of organoids in modeling complex disease phenotypes and facilitating mechanistic studies.
Main Methods:
- Tested 16 distinct chemical, physical, and cell functional manipulations in mouse retina organoids.
- Induced specific pathologies using factors like HBEGF and TNF, and analyzed combined effects.
- Utilized pharmacological inhibitors targeting MAPK, Rho/ROCK, NFkB, and CDK4 signaling pathways.
Main Results:
- Certain manipulations successfully induced differential phenotypes, confirming organoids' ability to model distinct pathologies.
- Combined application of HBEGF and TNF in organoids replicated complex pathologies, including photoreceptor neurodegeneration and glial damage.
- MAPK signaling inhibitors completely prevented both photoreceptor and glial pathologies; other inhibitors showed differential effects.
Conclusions:
- Mouse retina organoids effectively reproduce distinct and complex pathological processes relevant to neurodegenerative diseases.
- These organoid models provide mechanistic insights and can guide further optimization of organoid systems.
- Organoids are valuable tools for modeling differential phenotypes, aiding future fundamental and translational medicine research.
