Stem Cell for Retina Repair: Dr. David Gamm Research

Stem cell for retina repair: scientists grow basic retina structures from blood stem cells. We take it for granted, but our sense of seeing is nothing less than phenomenal. In split seconds, light bounces off what we see and goes through a number of processes before it’s “seen” as an image by our brains.

First, light has to reflect off an object, enter the eye, then pass through a thin veil of tears to the cornea, which focuses it.

Focused light then passes through a clear, watery fluid — the aqueous humor — then through the pupil, a central circular opening in the iris, the eye’s colored part. There, the amount of light that enters deeper into the eye is increased or limited by the contracting or dilating of the iris. From the pupil, light then goes through the lens, which focuses it further by changing shape.

This highly focused light, beamed through to the center of the eye, is then bathed in a clear jelly — the vitreous — that is surrounded by the retina, the back of the eye’s inner lining. The retina is like a movie screen, and the light is projected onto its flat, smooth surface.

Light then reaches the bull’s-eye at the retina’s center called the macula — and it’s only now that it finally reaches its final destination: the photoreceptors. These are specialized nerve endings that are light sensitive and convert the light into electrochemical signals. Meanwhile, beneath the photoreceptors, a layer of dark tissue known as the retinal pigment epithelium or RPE absorbs excess light so that the photoreceptors can give a clearer signal.

Signals sent from the photoreceptors travel along nerve fibers to the optic nerve — a nerve bundle that exits the back of the eye. The optic nerve sends the signals to the visual center in the back of the brain. It’s there in the brain that light is interpreted or “seen” as an image.

It’s these light-sensitive photoreceptor cells in the retina, found along the eye’s back wall, that produce the impulses transmitted to the brain that are largely responsible for allowing you to see.

It isn’t surprising then that vision loss is often related to damage to the retina. This is the case in retinal damage due to diabetes, age-related macular degeneration, retinal detachment or retinitis pigmentosa, a prominent cause of blindness in children and young adults, as well as other conditions.

Now scientists from the University of Wisconsin have made a breakthrough in research that gives many people with eye damage hope that their vision could someday be repaired.

For the first time, the UW researchers have created basic retina structures, containing proliferating neuroretinal progenitor cells — and have shown that these cells can mimic the human retina and form layers of cells that can allow them to communicate information, just like the retina does.

The progenitor cells were made using induced pluripotent stem (iPS) cells derived from human blood cells.

Specifically, at 72 days, the stem cells in the lab formed an early retina structure, with specialized cells resembling photoreceptors in the outer layer and ganglion cells in the inner layer.

Starting from a routine blood sample from a patient, it’s possible to create the more complex retinal tissues from human retinal cells — that’s what the findings of two experiments done by the UW team suggests. The researchers were led by Dr. David Gamm, Assistant Professor of Ophthalmology and Visual Sciences in the UW School of Medicine and Public Health.

In the first experiment, done in 2011, Dr. Gamm’s team at the UW Waisman Center used embryonic stem cells and stem cells derived from human skin to create structures comprising the most primitive stage of retinal development. The newly created structures then went on to generate the major types of retinal cells, including photoreceptors — but they lacked the organization found in more mature retina.

For the new research, Dr. Gamm and postdoctoral researcher and lead author Dr. Joseph Phillips gathered blood with standard blood draw techniques and used their method to grow retina-like tissue from iPS cells derived from this blood.

About 16 percent of the initial retinal structures went on to develop distinct layers that followed the precise arrangement of cells found in the back of the eye: the outermost layer contained photoreceptors, the middle developed intermediary retinal neurons, and the inner layers developed ganglion cells.

Even better, work by Dr. Phillips showed that these retinal cells were capable of making the synapses needed to communicate with each another.

Taken together, the two experiments comprise a breakthrough, with lab-built human retinal tissues having a number of important applications:
• These new tissues can be used to test medications and to study degenerative diseases of the retina
• If developed well enough in future experiments, the tissues may be used to replace multiple layers of the retina to help patients with more widespread retinal damage

“We don’t know how far this technology will take us,” says Dr. Gamm, a pediatric ophthalmologist and senior author of the study. “But the fact is that we are able to grow a rudimentary retina structure from a patient’s blood cells is encouraging — not only because it confirms our earlier work using human skin cells, but also because blood as a starting source is convenient to obtain.”

“This is a solid step forward,” Dr. Gamm says. His team’s findings are published in the March 12 online issue of Investigative Ophthalmology & Visual Science, the journal of the Association for Research in Vision and Ophthalmology.

The iPS cells used in the study were generated through a collaboration with Cellular Dynamics International (CDI), Madison, Wisconsin-based biotech company that pioneered the technique to convert blood cells into iPS cells. The company was founded by UW stem cell pioneer Dr. James Thomson.

“We were fortunate that CDI shared an interest in our work. Combining our lab’s expertise with that of CDI was critical to the success of this study,” says Dr. Gamm.

The CDI scientists extracted a type of blood cell called a T-lymphocyte from donor blood samples, and reprogrammed the cells into iPS cells.

The (iPS) cells or iPSCs were made by treating the human blood cells with reprogramming factors to revert them to an embryonic-like state. Like the stem cells in human embryos, iPS cells are can form any tissue in the body— including retinal cells—and on top of that, their use for experiments isn’t as controversial.

Other members of the research team include:
• Kyle Wallace, Amelia Verhoeven, Jessica Martin, Lynda Wright, Wei Shen, Elizabeth Capowski and Enio Perez, of the Waisman Center
• Sarah Dickerson and Michael Miller of CDI
• E. Ferda Percen of the Faculty of Medicine, Gazi University, Ankara, Turkey
• Xiufeng Zhong and Maria Canto-Soler, of the Wilmer Eye Institute at Johns Hopkins Univerity

The National Institutes of Health, the Foundation Fighting Blindness, the Retina Research Foundation, the UW Institute for Clinical and Translational Research, the UW Eye Research Institute and the E. Matilda Ziegler Foundation for the Blind, Inc. all funded the research.

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