Glial cells are the most abundant cell types in the central nervous system. Müller cells are the most common type of glial cells found in the retina. For a dozen years, Malia Edwards has been studying the role of Müller cells in retinal vascular development and retinal disease — specifically, age-related macular degeneration (AMD). AMD is the most common cause of severe loss of eyesight among people 50 and older, and at present, there is no cure. For the most common form of the disease, dry AMD, there is no treatment at all.

As Edwards explains, Müller cells, like all glial cells, surround neurons and provide support for and insulation between them. In the retina, Müller cells are important for maintaining a normal environment. But in AMD, the retinal environment is anything but normal. “We found that in AMD, the Müller cells, which are normally very linear structures, lose their linear formation and start to go places where they don’t normally go,” Edwards says. In some cases, the remodeled cells actually exit the retina and create membranes above and below the retina. Edwards suspects that these membranes may be inhibiting current treatments. “If we can understand what makes them form and possibly help prevent them from forming, we might also be able to improve current treatments,” she says.

But there’s another intriguing angle to Edwards’ research: When the remodeled Müller cells exit the retina, they interact with cells they are normally separated from — namely, the retinal pigment epithelial (RPE) cells at the edge of the diseased area, where the disease is progressing.

In her lab, Edwards is investigating how early in the disease process Müller cell changes occur, and how their activation and remodeling affects AMD disease progression by influencing blood vessels, neurons and RPE cells. “My hypothesis is that because the other cells are so dependent on Müller cells, if the Müller cells start to remodel or change their phenotype — their normal characteristics — early in the disease process, and start to push out things such as cytokines that promote inflammation or oxidative stress, they could ultimately be contributing to the disease,” she says.

For years, Müller cells were thought of as more of the glue that keeps everything together, more important for homeostasis and for keeping things normal. “No one really looked at these cells in this way,” says Edwards. “Even though we know that they respond very quickly in disease, their responses have always been presumed to be secondary. Now people are starting to catch on that even though it’s a secondary response, they could be contributing to the overall pathology.”

Edwards and her team recently completed a large single-cell sequencing project that allows them to see changes that occur in Müller cells at the genetic level when specific genes are upregulated or downregulated. She hopes that they can then show how this affects the Müller cells’ relationship with other cells, such as RPEs. “If we can decrease the Müller cell activation or response, does that help or hurt the pathology downstream? Does it slow disease progression, or increase it?” Eventually, she says, Müller cells may prove a target for helping to treat AMD.

She believes that the mechanisms behind the glial changes are also implicated in other retinal diseases such as retinitis pigmentosa and diabetic retinopathy. They may have implications for stem cell transplantation in the retina, as well: Edwards suspects the membranes would not only impair stem cells’ ability to get into the retina where they need to go, but may also prevent normal regenerations that would otherwise occur.

Lately, Edwards is in the process of merging her lab with that of her beloved mentor, Dr. Gerard Lutty, who passed away last year. Lutty is renowned for his work on the choroid — the eye’s vascular layer between the retina and the sclera — and had been investigating the role of choroidal mast cells in disease processes. Now Edwards is charged with focusing on Müller cells and mast cells, two different cells that she says share a common theme: they’re both “underdog” cells, understudied yet important in our understanding of eye disease. “It makes sense, because Dr. Lutty was the champion of the underdog, both in people and in the cells he studied for years,” Edwards says, alluding to his penchant for mentoring young scientists. “No one thought about the choroid before he started working on it, and he really put it on the map, and the same with mast cells and AMD in recent years.”