February 2010




Retinal stem cell work: More than skin deep

by Maxine Lipner Senior EyeWorld Contributing Editor


New protocol creates retinal cells from the skin

Microscopic photograph of early retinal cells (green) and early brain cells (blue) Source: David M. Gamm, M.D., Ph.D.

One day damaged retinas may owe their repair to skin cells. Results published in the Aug. 24, 2009, issue of the Proceedings of the National Academy of Sciences indicate that human stem cells made from the skin, dubbed induced pluripotent stem (iPS) cells, can be made to follow a process that very closely mimics normal human retinal development.

These could eventually be used not only for transplantation but to help better explain human retinal development, according to David M. Gamm, M.D., Ph.D., assistant professor of ophthalmology and visual science, School of Medicine and Public Health, University of Wisconsin-Madison, Madison. “We aren’t able to do the same types of experiments to understand retinal development in humans as we do in other animals,” he said. “This gives us not a perfect way but perhaps one of the better ways to try and understand that.”

Initially Dr. Gamm’s work was directed toward available stem cell lines. However, he found that the long range potential of these cells was limited. “We found that while we did have the capacity to produce cell types of interest, particularly photoreceptors for a very short period of time, when we expanded them in culture to the point where we could actually use them, they quickly lost their potential to produce retinal neurons, at least in our hands,” Dr. Gamm said.

Less developed cells

Instead the group decided to change focus and use cells from a less developed stage. “Let’s say what you really want is point S. By using a particular type of tissue, such as developing tissue, you’re already at point W so you have to push this back to where you want it to be,” he said. “The other option is to start earlier at a more primitive state and see if you can coerce them forward.”

With that in mind, Dr. Gamm and fellow investigators turned to embryonic stem cells. They built on the work of Su-Chun Zhang, M.D., researcher, Waisman Center, University of Wisconsin-Madison, who had developed a protocol for making embryonic cells into very early neural progenitors. “That’s the substrate from which the eye fields and the retina develop,” Dr. Gamm said. “We determined that he already had a protocol that gets us to first base.”

Dr. Gamm used a very minimalistic protocol involving a mechanical process in concert with medium and serum supplements. “It had to do with how the cells were handled—when they were plated down, when they were allowed to grow flat, and when they were lifted up to grow as spheres in a suspension culture,” Dr. Gamm said.

Using this minimalistic approach Dr. Gamm found a very high percentage of the cells were driven in the retinal direction. “The nice thing about this [minimalistic approach] is that it allows us without any factors to confound things to get a starting position,” Dr. Gamm said. “If we add a particular factor and it improves our efficiency of making a particular cell type, we now can dissect why that is, instead of just doing a shot gun approach.”

Results with the approach were very promising. “Not only did we show that we can obtain retinal pigment epithelium and photoreceptor rod and cone-like cells, but that we could do that in such a way that the sequence and timing was nearly exactly what we would predict from normal human development,” he said. “It seemed in the dish to intrinsically know the order and timing with which to accomplish that series of steps.”

Turning to the skin

In November 2007, when James Thompson, University of Wisconsin, created neural stem cells from skin, Dr. Gamm was intrigued. “We decided to take these and see if they’re really close to embryonic stem cells,” he said. “We applied the same protocol and followed them the same way that we followed the embryonic stem cells.” Dr. Gamm was gratified to find that they did appear to follow a strikingly similar course. “They were capable of doing pretty much exactly the same thing,” he said. “The fact that we can recapitulate that very complex sequence and timing and that it’s the same between the two is some of the strongest evidence thus far that iPS cells truly do behave similarly in principle to embryonic stem cells.”

Dr. Gamm sees the work as taking several different turns. “From a basic science standpoint I think that it allows us a model to better understand the mechanism by which retinal cells are created,” he said. “From a translational standpoint it provides an opportunity to obtain retinal cells for drug testing as well as perhaps for transplantation.”

He views using the iPS cells in particular as intriguing because these can be taken from the patient’s skin. “If we can take patients who have specific retinal diseases and potentially make models not just of development but of certain diseases, we can test drugs, mechanisms, and pathophysiology to better understand how diseases affect photoreceptors and retinal pigment epithelium,” Dr. Gamm said.

Ultimately, he sees the work as benefiting patients with diseases such as age-related macular degeneration and retinitis pigmentosa. He thinks that within five years the technology may be within reach. “I would think that in five years we’ll be at least starting to see if pluripotent stem cell technology might have a role for treatment of retinal degenerative disease,” Dr. Gamm said.

Editors’ note: Dr. Gamm has no financial interests related to his comments.

Contact information

Gamm: 608-261-1516, dgamm@wisc.edu

Retinal stem cell work: More than skin deep Retinal stem cell work: More than skin deep
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