Retina Transplants from Stem Cells

Human embryonic stem cells can be coaxed into three-dimensional structures of retinal cells.

By Courtney Humphries
From Technology Review (published by MIT)


Scientists have created a three-dimensional, retina-like structure out of human embryonic stem cells that they hope could someday serve as a retinal transplant for people with macular degeneration and other diseases of the retina. Their method, published recently in Journal of Neuroscience Methods, offers a potential new source of cells for retinal transplants.
Hans Keirstead, lead author of the paper and a stem cell biologist at University of California, Irvine, says that the method is designed to provide an alternative to human fetal tissue transplants, which have been conducted on a small group of patients and have resulted in improved vision. Fetal cells are difficult to obtain and raise ethical issues. "We really wanted to build upon that technique by creating a renewable source of tissue," he says.

In this study, the researchers first created two types of cells from the human embryonic stem cells: early-stage retinal cells, and retinal pigment epithelium (RPE) cells, which provide nourishment to the cells responsible for vision in the retina. The researchers then grew these two types of cells together in a chamber designed to expose them to a gradient of concentrations of solutes and growth-promoting chemicals. The cells could form three-dimensional structures, a feat rarely achieved with stem cells.

Keirstead believes that the study points to two important strategies for creating retinal transplants: growing early retinal cells along with RPE cells, and bathing the cells in a gradually changing solution that encourages the development of three-dimensional layers of cells. His team found that this approach generated early-stage retinal cells that were on the path of differentiating into all of the various cell types in the retina.

Keirstead believes that a retinal transplant will work best when made of cells that have not fully developed. "The three-dimensional layer is purposefully young," he says. Previous studies have found that younger cells are more likely to integrate with existing tissue after transplantation, rather than die.

Robert Lanza, chief scientific officer at Advanced Cell Technologies, who was not involved in the study, says that his team discovered several years ago that, when turning human embryonic stem cells into RPE cells, other stem cells would spontaneously form layers, including patches of photoreceptors. "This paper shows that you can take advantage of this natural process, and for the first time use tissue engineering techniques to generate three-dimensional retina-like structures," he says.

But Lanza is skeptical about the clinical usefulness of such structures. "You can't just transplant a retina and restore sight," he says, because it requires making a series of complex connections with the brain. Although he says there could prove to be some advantage to using three constructs of cells, "for the moment, replacing individual cell types might be the best approach for helping patients suffering from eye disease."

Scientists have been working on several approaches to retinal transplants. One approach, led by Advanced Cell Technologies, is to turn human embryonic stem cells into RPE cells and transplant them into the retina. The therapy would work best in the early stages of degeneration to halt further progress, rather than to restore vision that is already lost. Another approach is to transplant stem cells that are in the early stages of becoming light-sensitive photoreceptors, which has demonstrated efficacy in mice.
Yet another strategy is to use young tissue instead of individual cells. Fetal tissue transplants have shown some success in animals as well as a small group of humans. A study published in 2008 found that seven out of 10 patients who received the transplants had improved vision. However, there has been debate about whether these transplants actually integrate into the existing tissue. Keirstead has conducted a series of studies in animals that he says demonstrates that transplanted tissue is functioning in the eye. If so, the strategy could be useful for later-stage degeneration, when the existing retina has lost much of its function.

For Keirstead's team, the next step is to show that tissue derived from stem cells can function properly. His lab is currently transplanting the tissue into rats to determine whether the transplants can survive and incorporate into the eye, and whether they improve the animals' vision.

Crafting Light-Sensing Cells from Human Skin

From Technology Review:

Photoreceptors created from induced pluripotent stem cells.
By Janelle Weaver

Think twice the next time you wipe a few flecks of dandruff from your shoulder. You might be shedding cells that may someday restore human vision.

Thomas Reh and colleagues at the University of Washington, in Seattle, have generated light-sensing retinal cells, called photoreceptors, from adult human skin cells. They then transplanted the cells into a mouse retina, showing that the photoreceptors integrated normally into the surrounding tissue. This technological feat raises hopes for the development of treatments for retinal diseases, such as retinitis pigmentosa and macular degeneration, which cause visual impairment or blindness in millions of people in the U.S.

Researchers used induced pluripotent stem (iPS) cell technology, activating a handful of genes in skin cells in order to revert them to a flexible embryonic state. They then used previously developed methods to differentiate the cells into photoreceptors. While Reh's team has done similar experiments using embryonic stem cells, iPS cells are a preferable source for cell replacement therapies because they can be derived from the patient. Skin cells are a ready source of cells that are tissue-matched to the recipient, bypassing problems associated with immune rejection of stem-cell transplants.

The cells also provide a new way to study retinal degeneration diseases and to identify drug targets. Retinitis pigmentosa, for example, is an inherited disorder in which the photoreceptors begin to die. Retinal cells derived from a patient with the disease harbor all the genetic mutations that contributed to the patient's disease, so scientists can try to determine the molecular mechanisms that lead to cell death. They can then use the cells to screen for molecules that can slow or stop the damage.

"There are no good drugs to slow photoreceptor degeneration," said Reh, a neurobiologist at the University of Washington. "One reason we don't have more molecules we can test is that we don't have good animal models for many human retinal diseases."

Scientists will still need to overcome some serious hurdles before using the cells for transplantation therapies. The genetic flaws that led to the disease would need to be fixed before implanting the cells into the eye. And researchers need to figure out how to get large volumes of cells to integrate effectively into the retina. In the current experiments, published last month in the journal PLoS ONE, the number of cells that took root in the mouse eye was too low to restore visual sensitivity. "We need about 10,000 cells to integrate into the retina for them to restore function," Reh said.

Future research will have to explore how well the transplanted photoreceptors connect with other cell types in the retina and function as an integrated circuit. "The work still ahead is huge," said Robert Lanza, chief scientific officer at Advanced Cell Technology. "But this is a very important first step."