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Engineered Human Brain Organoids Develops Primitive Eye Like Structures
(Photo Credit/Elke Gabriel)
Organoids have enabled the understanding of human physiology at the cellular and tissue level with unprecedented detail. Developed from healthy and diseased tissue samples or pluripotent stem cells, they help with identifying cellular diversity, interconnectivity, and cross-talk specific to their organ-of-origin.
Brain organoids are extremely informative in dissecting the extremely intricate and complex neuronal networks. In a new study, scientists from the Institute of Human Genetics, University Hospital of Düsseldorf, unraveled the developmental capabilities of brain organoids to form primitive structures of the eye. They used induced pluripotent stem cells (iPSCs) to form human brain organoids, which could further develop optic vesicles.
A Step Forward in the Field
Previous work on retinal organoids showed that they could not form optic vesicles and retinal pigment epithelial cells, suggesting that lack of forebrain could hinder further development since the forebrain is implicated in retinogenesis during development.
The team at the Laboratory for Centrosome and Cytoskeleton Biology had previously turned iPSCs into neural tissue. In this study, they modified the protocol and generated 3-dimensional brain organoids with primary eye structures, such as an optic cup, after 30 days of culturing.
The optic-vesicle containing brain organoids (OVB-organoids), developed after 50-60 days of culturing, could represent the fundamental structure of the brain-eye network. This timeline is crucial in that it mimics the development of an immature neural retina in the human embryo.
The OVB-organoids contain an array of optic cells as demonstrated by markers and transcriptome sequencing, which includes corneal epithelial cells, lens-like cells, retinal pigment epithelial cells, and retinal progenitor cells. They also had microglia, cortical neurons with axon-like formations, and functional neuronal networks that responded to light with electrical activity.
Comparison of OVB-organoids with fetal retina and retinal organoids showed significant overlap, despite substantial brain tissue in OVB-organoids, indicating the requirement of the brain for optimal retinal development in vitro. The method was reproducible with experiments in over 300 brain organoids across 16 independent batches, with 72% organoids forming optic cups.
Future Directions
While this study demonstrates that brain organoids can form bilaterally symmetric optic vesicles, further work is needed to understand the mechanism that contributes to this spatial arrangement. The viability of the organoids beyond 60 days was not robust, limiting the development into mature retinal cell types.
However, the study demonstrated that 3D organoids from iPSCs can provide insights into embryonic development to understand the integration of neuronal networks and visual systems. It can empower developmental neurobiology experiments to understand the brain-eye network during early development.
“Our work highlights the remarkable ability of brain organoids to generate primitive sensory structures that are light sensitive and harbor cell types similar to those found in the body. These organoids can help to study brain-eye interactions during embryo development, model congenital retinal disorders, and generate patient-specific retinal cell types for personalized drug testing and transplantation therapies,” senior study author Jay Gopalkrishnan told EurekAlert!
Prof. Jay Gopalakrishnan is a German scientist of Indian origin, who attained his bachelor’s and master’s degrees in India. He is presently the group leader of the Laboratory for Centrosome and Cytoskeleton Biology, at the University Hospital of Düsseldorf. His group is interested in understanding the basic principles of centrosomes and cilia biogenesis. Their research focuses on dissecting how centrosomes and cilia function as molecular switches in determining homeostatic control of neural stem cells.
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