Embryonic stem cells and diseases of the retina

Seeing begins with photoreceptors, the cells that convert light into signals that the brain translates into the images that we see. Those photoreceptors’ lives depend on a layer of cells at the back of the eye called the retinal pigment epithelium (RPE). “You can think of RPE as a nurse that keeps photoreceptors happy and functioning. If RPE gets sick and dies, photoreceptors get sick and die,” said Lawrence Rizzolo, Ph.D., professor of surgery (gross anatomy) who also runs a lab in Yale’s Stem Cell Center. “It happens the other way, too. If photoreceptors die, RPE—not having photoreceptors to interact with—dies, too.”

As part of their day-to-day operations, photoreceptors shed some of their light-capturing membranes and acquire new ones. RPE eats the discarded membranes, clearing them from the eye. “If that doesn’t happen, you get all this debris in the retina that isn’t degraded, and retinal diseases occur,” Rizzolo said. Those diseases are some of the leading causes of blindness, including macular degeneration, diabetic retinopathy, and retinitis pigmentosa.

RPE’s critical role in maintaining the health of photoreceptors makes this layer of cells a potential target for treatment of these blinding diseases of the retina. Researchers in Rizzolo’s lab are using human embryonic stem cells to bioengineer RPE and retinal progenitor cells (RPCs). They hope one day to implant the cells and restore sight to people with certain types of vision loss.

Animal studies have shown that implanting stem cell-derived RPE in the eye in the early stages of disease could replace host RPE and slow vision loss. But later in the disease, the procedure does not yield the same benefits. In order for RPE transplant to gain traction as a treatment option, Rizzolo says, it needs to be available to patients who have begun to lose some vision and are willing to take the risk of surgery. “Suppose you see okay now, and you’ll probably see okay for another 10 years, but then I told you things are going to get worse, and if this procedure works, we’ll slow that down—but if it doesn’t work, you could go blind tomorrow because, after all, it is still surgery and a difficult one.”

That’s not the only challenge for Rizzolo and other researchers. As embryonic stem cells differentiate to become RPE cells, they need RPCs nearby to shepherd them through the process and vice versa. For full function of both tissues, they need to co-differentiate.

To address this problem, Rizzolo is growing RPE cells on a matrix alongside retinal progenitor cells. He and other researchers still need to find a way to grow this retinal tissue in a flat sheet that mimics a normal human retina. “When you grow retinal progenitor cells, they grow as tiny spheres that don’t undo themselves when you transplant them,” said Rizzolo. Because these light-sensitive cells, which don’t work without physical contact with RPE, are trapped inside those tiny spheres, RPE cannot keep them alive.

Rizzolo and his team have developed a gelatin-based scaffold in which to suspend RPCs and present them to RPE as a flat sheet. So far, the scaffold has allowed his team to produce flat, sheet-like retinal tissue.

The question now is, if researchers implant the retinal cells later in the progress of the disease, will they still slow it down or better yet, reverse it? “Those experiments are in progress,” Rizzolo says.

Rizzolo’s team and physicians at the Yale Eye Center will try the procedure on a live pig who underwent retinal laser burns that simulate macular degeneration. After surgery, the pig will undergo tests to reveal whether its eyes have resumed normal communication with the brain.

“If the signal gets to the visual cortex in the back of the brain, this will tell me that not only did I reinstate circuits in the retina, but those circuits are sending information to other parts of the brain.”