Research News

Zebrafish have a remarkable ability to regenerate retinal neurons damaged by acute injury. Unlike humans, they can regrow photoreceptors and restore their visual function. Conventional belief is that mammals don't have this ability. Retinal damage in humans, and the associated vision loss, is permanent. 

"We don't know why photoreceptors don't regenerate in humans," says ophthalmic researcher Brian Perkins, PhD, Department of Ophthalmic Research. "Do human retinas completely lack the ability, or is the cellular machinery there but just not activated?" 

Dr. Perkins and his lab at Cleveland Clinic have been exploring this concept for more than a decade - building a foundation for potential retinal rewiring in humans. They hope to get one step further thanks to a new $2.1 million, four-year research grant from the National Eye Institute, studying the role of inflammation in retinal regeneration in zebrafish. 

Learning how chronic disease impacts retinal regeneration in a species that normally does regenerate may reveal new insights into retinal regeneration in humans with chronic retinal disease. 

Today, patients with inherited retinal dystrophies typically progress to some level of permanent vision loss. While some gene therapies show great promise, they are targeted to specific mutations of specific genes. For the majority of people with inherited retinal dystrophy, therapeutic options are limited.

The inflammation influence 

In 2022, the Perkins team published a study that showed how the expression of one particular gene in zebrafish triggered retinal regeneration. When the gene was turned off, Müller glia cells in zebrafish retinas would reprogram and divide to produce neuronal progenitor cells, which would proliferate and differentiate into mature neurons.

But this only happened in the presence of inflammation. Preventing inflammation would prevent the process. 

"There was a nuance to it," explains Dr. Perkins. "There had to be a wave of initial inflammation that would soon get resolved. We learned that pro-inflammatory signaling was essential to initiate Müller glia proliferation, but resolving the inflammation was necessary for the survival and differentiation of neural precursors." 

In other words, to enable retinal regeneration in zebrafish, inflammation couldn't be too little or too much, but just right. This may explain why zebrafish regenerate retinal neurons following acute injury but not in a model of chronic disease that produces long-term inflammation. 

"The difference between injury and disease is not well understood, so that's what we're going to explore over the next four years," says Dr. Perkins. "Our work could be valuable in the development of strategies to induce retinal regeneration in humans, who more commonly have retinal damage due to a chronic disease, not an acute injury." 

Story originally posted on ConsultQD. Read more here.