Brain organoids have helped unravel the understanding of cellular diversities, complex interactions, and neuronal networks. Human-induced pluripotent stem cells (iPSCs) can be used to generate brain organoids containing the optic cup—a structure that gives rise to the retina. Now, new research shows that the optic vesicle-containing brain organoids (OVB organoids) develop bilaterally symmetric optic vesicles and are light sensitive. The research team behind the work plans to develop strategies to keep the optic cups viable for long time periods, using them to investigate mechanisms that cause retinal disorders.

This work is published in Cell Stem Cell in the paper, “Human brain organoids assemble functionally integrated bilateral optic vesicles.

Eye development is a complex process, the authors wrote, and understanding it could allow underpinning the molecular basis of early retinal diseases. Thus, they continued, it is crucial to study optic vesicles that are the primordium of the eye whose proximal end is attached to the forebrain, essential for proper eye formation.

“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,” said Jay Gopalakrishnan, PhD, group leader of the Laboratory for Centrosome and Cytoskeleton Biology at the the University Hospital Düsseldorf. “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.”

This image shows a brain organoid with optic cups. [Elke Gabriel]
Many aspects of human brain development and diseases can be studied using 3D brain organoids derived from pluripotent stem cells, which can give rise to all cell types in the body. Researchers previously used human embryonic stem cells to generate the optic cup, which gives rise to the retina—the light-sensitive layer of tissue at the back of the eye. Another study demonstrated that optic-cup-like structures can be generated from iPSCs, which are derived from adult cells that have been genetically reprogrammed back into an embryonic-like pluripotent state.

In the past, the production of optic cups from pluripotent stem cells focused on generating the pure retina. Until now, optic cups and other 3D retinal structures had not been functionally integrated into brain organoids.

To achieve this feat, Gopalakrishnan and his team modified a protocol they previously developed for turning iPSCs into neural tissue. The organoids spontaneously developed bilaterally symmetric optic cups from the front of the brain-like region, demonstrating the intrinsic self-patterning ability of iPSCs in a highly complex biological process. The human brain organoids formed optic cups, which appeared as early as 30 days and matured as visible structures within 50 days. This timeframe parallels that of retinal development in the human embryo and could make certain types of developmental neurobiology experiments more efficient.

Across 16 independent batches from four iPSC donors, the researchers generated 314 brain organoids, 72% of which formed optic cups, showing that the method is reproducible. These structures contained diverse retinal cell types, which formed electrically active neuronal networks that responded to light. The optic cup brain organoids also contained lens and corneal tissue and exhibited retinal connectivity to brain regions. “In the mammalian brain, nerve fibers of retinal ganglion cells reach out to connect with their brain targets, an aspect that has never before been shown in an in vitro system,” Gopalakrishnan said.

Graphical abstract Gabriel et al.
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