The key to zebrafish regenerating retinal tissue may lie within their microglia cells, according to scientists from Johns Hopkins University School of Medicine.
The NEI-funded study, published April 2017 in the Proceedings of The National Academy of Sciences, offers new insights into how regeneration may occur in human eyes. As surprising as it may sound, the physiologic leap from small aquarium fish to a human subject is short, thanks to a long list of shared ocular mechanisms preserved during evolution from a common ancestor.
“At the cellular level, zebrafish and human eyes are remarkably similar,” says Jeffrey Mumm, PhD, principle investigator and associate professor of ophthalmology at Johns Hopkins.
For example, both human and zebrafish retinas contain Müller glia. However, the glia in zebrafish possess the ability to convert into stem cells in response to injury, whereas their human counterparts do not.
"Humans have an evolutionary block on our ability to regenerate certain tissues," Dr. Mumm said. "But humans still have the genetic machinery needed to regenerate retinal tissue, if we can activate and control it."
In this study, researchers relied on zebrafish model to examine the immune system’s role in retinitis pigmentosa. After initiating photoreceptor loss, they used fluorescent labeling to track the activity of 3 types of immune cells—neutrophils, microglia and peripheral macrophages. They found that neutrophils and peripheral macrophages either did not respond or were unable to penetrate the blood-retinal barrier. Microglia, however, were able to both respond to the injury and reach the dying cells.
“We could see the peripheral macrophages wanted to do something, but could not gain access. Neutrophils didn’t even detect that something had happened, but the microglia were at the right place at the right time,” says Mumm.
Building upon their initial findings, the team conducted further tests by ablating both photoreceptors and microglial cells to determine the role of microglia during regeneration. The loss of microglial cells in zebrafish almost completely suppressed the regenerative activity of Müller glia for 3 days, compared with approximately 75% regeneration in the control population with intact microglia.
Additionally, researchers found that they could improve the Müller glia’s regenerative response and accelerate the growth of new tissue in the retina by adding dexamethasone to the tank water. They hypothesize that the steroid’s anti-inflammatory effects may trigger microglia cells to transition from an M1 phase—which is associated with inflammation—to an M2 phase, which is associated with repair.
In total, the findings suggest that microglia affect the Müller glia’s regenerative response and can be harnessed to accelerate the growth of new retinal tissue.
Although the study offers great promise, Dr. Mumm cautions that his team was able to track only 3 types of immune cells, and there may be other innate immune cells involved in this process that they couldn’t observe.
The team plans to improve its imaging techniques to facilitate further research on how immune cells can impact the regeneration process.