PEDF in the Retina, an Example of the Slow Pace of Progress
Fifteen years ago, initial clinical trials were underway for a gene therapy to upregulate PEDF expression in the retina of patients with macular degeneration, the result of years of work on the involvement of PEDF expression in retinal aging. Today, we can see researchers still working with animal models on the fundamental question of whether or not PEDF expression is actually relevant in the aging of the retina. This sort of thing isn't uncommon. Research into the role and relevance of any given protein can span decades, and still go nowhere. This is not a field noted for its speed, or its ability to focus on approaches that work well versus those that are marginal.
The retina is composed of layers of cells that function together to detect and process light signals, which the brain uses to generate vision. The retina's light-sensing photoreceptors sit above the retinal pigment epithelium (RPE), a layer of support cells. The RPE nourishes photoreceptors and recycles pieces of the photoreceptor cells called "outer segments," which get used up and their tips shed each time photoreceptors detect light. If the RPE cannot provide recycled components of older outer segment tips back to photoreceptors, these cells lose their ability to make new segments, and eventually become unable to sense light. And without nutrients supplied by the RPE, photoreceptors die. In people with macular degeneration or certain types of retinal dystrophies, senescence, or death of RPE cells in the retina leads to vision loss.
Previous work has shown that PEDF protects retinal cells, preventing both damage to the cells and abnormal growth of blood vessels in the retina. RPE cells produce and secrete the PEDF protein. The protein then binds to its receptor, PEDF-R, which is also expressed by RPE cells. Binding by PEDF stimulates PEDF-R to break down lipid molecules, key components of the cell membranes that enclose photoreceptor outer segments and other cellular compartments. This breakdown step is a key part of the outer segment recycling process. And while researchers have known that PEDF levels drop in the retina during the aging process, it was not clear whether this loss of PEDF was causing, or merely correlated with, age-related changes in the retina.
To examine the retinal role of PEDF, researchers studied a mouse model that lacks the PEDF gene, finding that the RPE cell nuclei were enlarged, which may indicate changes in how nuclear DNA is packed. The RPE cells also had turned on four genes associated with aging and cellular senescence, and levels of the PEDF receptor were significantly below normal. "One of the most striking things was this reduction in the PEDF receptor on the surface of the RPE cells in the mouse lacking the PEDF protein. It seems there's some sort of feedback-loop involving PEDF that maintains the levels of PEDF-R and lipid metabolism in the RPE."