Seeing the future: Zebrafish regenerates fully functional photoreceptor cells and restores its vision

(Image Credit: AdobeStock/NERYX)

A wide range of blinding diseases damage photoreceptor cells that humans cannot naturally regenerate, leading to permanent vision loss.

Researchers continue to work on way to replace or regenerate these cells, but a key question is whether these regenerated photoreceptors can fully restore vision. Now, a team of researchers led by Michael Brand, PhD, at the Center for Regenerative Therapies Dresden (CRTD) of Dresden University of Technology has made strides in this area.

Brand’s team has studied zebrafish, an animal naturally capable of photoreceptor regeneration. The researchers have demonstrated that regenerated photoreceptors are as good as original ones and regain their normal function, allowing the fish to recover complete vision. Their results, published in the journal Developmental Cell, show insights for the future of photoreceptor replacement therapies.

In the retina, photoreceptor cells capture light and convert it into electrical signals. For humans, these photoreceptors are not replaced after damage. Once lost, they do not regenerate, leading to irreversible vision loss.¹

According to a news release. researchers continue to work on therapies, including at the CRTD in Dresden, with a goal of replacing damaged human photoreceptors and restoring vision, either by stimulating stem cells within the retina to develop into new photoreceptors or by transplanting photoreceptors that have been grown outside of the body.

Unlike humans, zebrafish can regenerate parts of their nervous system even after severe damage. Zebrafish can regenerate photoreceptors from special stem cells located in the retina, known as Müller glia. This ability makes zebrafish an ideal model for studying the potential to restore vision through photoreceptor regeneration.¹

Brand, who research group leader at the CRTD who led the study, pointed out that mammalian retina, including human retina, has very similar Müller glia cells.

“However, our cells have lost the ability to regenerate during evolution. Since these cells are so very similar, however, it may be possible to rekindle this regeneration potential for therapeutic applications in the future,” Brand said. “However, it is crucial to determine if such new photoreceptor cells can function as effectively as the originals.”

It has long known by researchers that zebrafish can regenerate damaged retinas, with new photoreceptors appearing identical to the originals. Various groups, including Brand’s group, came up with behavioral tests that confirmed that fish regained vision after regeneration. But these tests could not directly assess the extent to which the photoreceptor function was restored.¹

Brand pointed out in the news release the only test to see if the vision is fully restored is to directly measure the electrophysiological activity of the retinal cells.

“Are photoreceptors correctly stimulated by the various colors of light? Are they electrically active to the same extent? Are they connected to the neighboring cells? Are they passing the signal to them? Are all the typical circuits engaged?” Brand said.

In an effort to answer these questions, Brand’s team used a genetically modified zebrafish that let them use high-end microscopy to track the activity of photoreceptors at the photoreceptor synapse, i.e., directly where photoreceptors hook up to other nerve cells and move the electric signal forward.

Zebrafish photoreceptor cells stimulated with blue light show correct electrical activity. The picture was taken using the microscope that was custom-built for this study. (Image credit: Michael Brand and Evelyn Abraham)

The researchers found that testing the function of regenerated photoreceptors proved to be a significant technical challenge. Photoreceptors convert light into electrical signals. The researchers knew that when they used light to observe cells under the microscope, the simultaneously stimulated them. This technical difficulty seemed almost impossible to overcome.

With input from Tom Baden, PhD, from the University of Sussex in Brighton, United Kingdom, and Hella Hartmann, PhD, leader of the Light Microscopy Facility at the Center for Molecular and Cellular Bioengineering at TUD, the team was able to build a custom microscope that allowed the researchers to uncouple the stimulation from observation and measurement for different light colors, and to overcome this technical hurdle.

Brand’s team of researchers used the custom setup to show that the regenerated photoreceptors indeed regain their normal physiological function. They respond to light at different wavelengths, transmit the electric signal to neighboring cells, and do so with the same sensitivity, quality, and speed as original photoreceptors in an intact retina.¹

“Restoring all of these aspects of photoreceptor function, together with our previous work on restoring vision-controlled behavior, confirmed on a molecular level that the fish can fully ‘see’ again,” Brand said in the news release.

Brand pointed out that humans and fish have a common evolutionary ancestry and share most of the genes and types of cells.

“We hope that humans can learn this ‘regeneration trick’ from the zebrafish. It is important to note that, at this stage, our work is classical basic research,” he said in the news release.

However, Brand noted that applying the research to the clinic is still a long way off.

“However, being able to eventually achieve such functional regeneration from stem cells already located in the human retina could potentially revolutionize the treatment of currently untreatable diseases like retinitis pigmentosa or macular degeneration,” he concluded. “This study brings us one step closer to that dream.”

Reference:

1. Evelyn Abraham, Hella Hartmann, Takeshi Yoshimatsu, Tom Baden, Michael Brand, Restoration of cone-circuit functionality in the regenerating adult zebrafish retina, Developmental Cell, Volume 59, Issue 16, 2024, Pages 2158-2170.e6, ISSN 1534-5807, Accessed August 30, 2024. https://doi.org/10.1016/j.devcel.2024.07.005.