Retina in a petri dish

In The Laboratory

A retina made in a laboratory in Japan could pave the way for treatments for human eye diseases, including some forms of blindness.

Created by coaxing mouse embryonic stem cells into a precise 3-D assembly, the “retina in a dish” is by far and away the most complex biological tissue engineered yet, scientists say. “There’s nothing like it,” says Robin Ali, a human molecular geneticist at the Institute of Ophthalmology in London who was not involved in the study.

“When I received the manuscript, I was stunned, I really was. I never though I’d see the day where you have recapitulation of development in a dish.” If the technique, published in Nature, can be adapted to human cells and proved safe for transplantation – which will take years – it could offer an unlimited well of tissue to replace damaged retinas. More  immediately, the synthetic retinal tissue could help scientists in the study of eye disease and in identifying therapies.

The work may also guide the assembly of other organs and tissues, says Bruce Conklin, a stem-cell biologist at the Gladstone Institute of Cardiovascular Disease in San Francisco, who was not involved in the work. “I think it really reveals a larger discovery that’s coming upon all of us: that these cells have instructions that allow them to self-organise.”

Cocktail recipe

In hindsight, previous work had suggested that, given the right cues, stem cells could form eye tissue spontaneously, Ali says. A cocktail of genes is enough to induce frog embryos to form eyes on other parts of their body, and human embryonic stem cells in a petri dish can be coaxed into making the pigmented cells that support the retina, sheets of cells that resemble lenses and light-sensing retinal cells themselves. However, the eye structure created by Yoshiki Sasai at the RIKEN Center for Developmental Biology in Kobe and his team is much more complex.

The optic cup is a brandy-snifter-shaped organ that has two distinct cell layers. The outer layer – that nearest to the brain – is made up of pigmented retinal cells that provide nutrients and support the retina. The inner layer is the retina itself, and contains several types of light-sensitive neuron, ganglion cells that conduct light information to the brain, and supporting glial cells.

To make this organ in a dish, Sasai’s team grew mouse embryonic stem cells in a nutrient soup containing proteins that pushed stem cells to transform into retinal cells. The team also added a protein gel to support the cells.

“It’s a bandage to the tissue. Without that, cells tend to fall apart,” Sasai says. At first, the stem cells formed blobs of early retinal cells. Then, over the next week, the blobs grew and began to form a structure, seen early in eye development, called an optic vesicle. Just as it would in an embryo, the laboratory-made optic vesicle folded in on itself over the next two days to form an optic cup, with its characteristic brandy-snifter shape, double layer and the appropriate cells.

Even though the optic cups look and develop like the real thing, “there may be differences between the synthetic retina and what happens normally,” Ali says. Sasai’s team has not yet tested whether the optic cups can sense light or transmit impulses to the mouse brain. “That’s what we are now trying,” he says. However, previous studies have suggested that embryonic retinas can be transplanted into adult rodents.

Sasai, Ali and others expect that human retinas, which develop similarly to those of mice, could eventually be created in the lab. “In terms of regenerative medicine, we have to go beyond mouse cells. We have to make human retinal tissue from human embryonic stem cells and investigation is under way,” Sasai says.

The eyes have it

Synthetic human retinas could provide a source of cells to treat conditions such as retinitis pigmentosa, in which the retina’s light-sensing cells atrophy, eventually leading to blindness. In 2006, Ali’s team found that retinal cells from newborn mice work when transplanted into older mice. Synthetic retinas, he says, “provide a much more attractive, more practical source of cells”.

David Gamm, a stem-cell biologist at the University of Wisconsin, Madison, says that transplanting entire layers of eye tissue, rather than individual retinal cells, could help people with widespread retinal damage. But, he adds, diseases such as late-stage glaucoma, in which the wiring between the retina and brain is damaged, will be much tougher to fix.

When and whether such therapies will make it to patients is impossible to predict. However, in the nearer term, synthetic retinas will be useful for unpicking the molecular defects behind eye diseases, and finding treatments for them, Sasai says. Retinas created from reprogrammed stem cells from patients with eye diseases could, for instance, be used to screen drugs or test gene therapies, Ali says.

Robert Lanza, chief scientific officer of the biotechnology company Advanced Cell Technology, based in Santa Monica, California, says the paper has implications far beyond treating and modeling eye diseases. The research shows that embryonic stem cells, given the right physical and chemical surroundings, can spontaneously transform into intricate tissues.

“Stem cells are smart,” Lanza says. “This is just the tip of the iceberg. Hopefully it’s the beginning of an important new phase of  stem-cell research.

Nature News