Eye Cells Believed to Be Retinal Stem Cells Are Misidentified

Cells isolated from the eye that many scientists believed were retinal stem cells are, in fact, normal adult cells, investigators at St. Jude Children's Research Hospital have found. If retinal stem cells could be obtained, they might provide the basis for treatments to restore sight to millions of people with blindness caused by retinal degeneration. Stem cells are immature cells capable of producing large numbers of adult cells, such as retinal cells. Researchers believe that stem cells offer the promise of regenerating tissue in organs such as the eye, brain and heart, damaged by trauma or disease.

The new findings suggest that research on cell therapies to restore blindness should not concentrate on these eye cells previously believed to be retinal stem cells. More promising, the scientists said, is research aimed at re-engineering stem cells to develop into the light-sensitive photoreceptor cells that are lost as a result of retinal degeneration. Such studies could lead to implantation of such engineered photoreceptor cells into the eye to restore sight.

Led by Michael Dyer, the researchers published their findings March 30, 2009, in the online early edition of the Proceedings of the National Academy of Sciences. Dyer is a member of the St. Jude Department of Developmental Neurobiology.

In studies reported in 2000, scientists proposed that the layer of ciliary epithelial cells lining the inside of the eye, contains retinal stem cells because when grown in culture dishes these cells formed tiny spheres of about a thousand cells, says Dyer, the paper's senior author. These spheres, in turn, could be cultured to give rise to more spheres, reminiscent of the self-renewing capability of stem cells. Also, the cultured sphere cells showed activation of genes characteristic of adult eye cells.

"The first clue that these cells were not stem cells was that they were pigmented," Dyer says. "Neural stem cells, in general, and retinal progenitor cells, in particular, are not pigmented. Nevertheless, the previous finding was met with a tremendous amount of enthusiasm because of the promise of introducing these cells into the eye to regenerate photoreceptors lost to blindness."

In their studies, Dyer and his colleagues analyzed the sphere-forming cells in detail to determine whether they were really retinal stem cells. Painstaking microscopy studies of each cell in the spheres revealed all were pigmented and had features of ciliary epithelial cells. The researchers also compared the structure of the sphere-forming cells with those of confirmed stem cells and other immature cells in the developing retina called progenitor cells. That comparison revealed fundamental differences between the sphere-forming cells and established stem or progenitor cells.

The researchers also found that simply culturing the sphere-forming cells in the same growth medium as is used for stem cells caused them to activate genes characteristic of stem cells, yet remain adult ciliary epithelial cells.

Dyer says that a particularly promising alternative is the possibility of taking samples of adult cells -- such as fibroblasts that form connective tissue -- from a patient with retinal degeneration and exposing them to genetic cues that induce them to revert to stem cells. Those induced pluripotent stem cells could then be manipulated to develop into light-sensing photoreceptor cells that could then be transplanted into the patient's eyes to restore vision.

"This approach would solve many problems of developing cell-based therapy for blindness," Dyer says. "First, these cells are immortal, so they can be grown indefinitely to produce large amounts of cells for treatment. And secondly, they would be immunologically matched to the patient, so there would be no danger of rejection. And thanks to some excellent research during the past 15 years, we know a lot about how to reprogram such stem cells to make them into photoreceptors."

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Reprogramming The Debate: Stem-cell Finding Alters Ethical Controversy

When University of Wisconsin-Madison researchers succeeded in reprogramming skin cells to behave like embryonic stem cells, they also began to redefine the political and ethical dynamics of the stem-cell debate, a leading bioethicist says. R. Alta Charo, a UW-Madison professor of law and bioethics, says the scientific finding could have far-reaching effects on the social dimensions of the ongoing controversy over embryonic stem cell research.

"This is a method for creating a stem cell line without ever having to work through, at any stage, an entity that is a viable embryo," Charo says. "Therefore, you manage to avoid many of those debates with the right-to life community."

The research alters the debates surrounding both human embryonic stem cell research and somatic cell nuclear transfer cloning. For ordinary embryonic stem cell research, it offers a means of obtaining pluripotent cell lines from a non-embryonic source. For cloning research, it offers a means to make customized, pluripotent cell lines without having to create an intermediate embryo that is a "clone" of an adult person, she says.

Charo says the discovery could remove objections from critics on both the right and left wings of the political spectrum.

To derive embryonic stem cells, it is necessary to remove critical cells from an embryo, resulting in its destruction. That triggers opposition from right-to-life critics of the research, who cite moral and ethical concerns. The research has also generated opposition from some members of the women's movement who object the use of stimulating drugs in women who agree to donate eggs for cloning research aimed at creating specialized embryonic stem cell lines.

The latest findings have the potential to render both of those objections moot, since the research showed that introducing four genes into cells derived from skin cells, called human fibroblasts, resulted in cells that essentially share all the features of embryonic stem cells - but without using or destroying embryos.

"It holds a great deal of promise for freeing this whole area of research from those two main sources of friction," Charo says. The discovery also creates questions about the future of government funding for traditional embryonic stem cell research, which in recent years has been a contentious political issue.

"It's going to fuel those who call for preferential federal funding only for non-embryonic stem cell research and it will certainly complicate any efforts to expand funding for embryonic stem cell research at the federal level," she says. Twice, Congress has passed legislation to overturn the Bush administration policy on embryonic stem cell research and allow funding for research using any embryonic stem cell lines, not just those designated by the administration in 2001. Twice, President Bush has vetoed it.

"Any piece of research like this that suggests that we can get cell lines that are equally usable without having to go through an embryo in intermediate steps is going to undermine any effort on the part of Congress to overturn the Bush policy," she says.

The latest discovery, however, is likely to suggest avenues of research that are already eligible for federal funding. Recently, the White House directed the National Institutes of Health to emphasize the funding of research that examines alternative means for obtaining pluripotent cell lines whose usefulness is comparable to that of human embryonic stem cells.

"No matter how well this new technique can be used for many of the disease-research and disease-treatment applications foreseen for embryonic stem cell and cloning research, however, calls for criminalization or wholesale de-funding of embryonic stem cell and cloning research are not warranted," Charo adds. "Criminalizing any area of science, as opposed to merely regulating it, would be contrary to the political and constitutional traditions of academic and scientific freedom, as well as the historical spirit of inquiry that characterizes this country."



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Consumer Groups File Comments Supporting Stem Cell Patent Rejection

Two consumer groups have filed comments with the U.S. Patent and Trademark Office supporting its rejection of human embryonic stem cell patent claims asserted by the Wisconsin Alumni Research Foundation (WARF) because the claimed advances are obvious in the light of previous stem cell research, the groups say.

Last July the groups, the Foundation for Taxpayer and Consumer Rights (FTCR) and the Public Patent Foundation (PUBPAT) challenged the patents because they are hindering stem cell research.

Four internationally known stem cell scientists, Douglas Melton of Harvard University, Alan Trounson of Monash University in Australia, Chad Cowan of Harvard University and Jeanne Loring of the Burnham Institute for Medical Research, filed declarations supporting the consumer groups and the PTO's earlier finding that the work done by James Thomson does not deserve a patent.

In papers filed on Friday, FTCR and PUBPAT say that although WARF has narrowed its claims and made several arguments in its response to the PTO "none of the Patent Owners' arguments have sufficient merit to overcome the rejections."

"I very much believe Dr. Thomson deserves the scientific and public recognition he has received," Melton's declaration says. "However, he deserves that recognition because he undertook the arduous and timely task of getting fresh and high quality embryos to use as starting material for his work, and sufficient funding for such research, not because he did anything that was inventive... His perseverance and commitment deserve recognition and accolades. But I believe that had any other stem cell scientist been given the same starting material and financial support, they could have made the same accomplishment, because the science required to isolate and maintain human embryonic stem cells was obvious."

WARF holds three stem cell patents, numbers '780, '806 and '913, based on work done by Thomson. The PTO granted the requests for re-examination and in March rejected all the claims of all three patents. WARF had the opportunity to respond to all three rejections. The rules applicable to the'913 case under a so called "inter partes" re-examination allow the challengers to comment on WARF's response in that proceeding.

"What Dr. Thomson did was admirable," says John Simpson FTCR Stem Cell Project director. "It just isn't patentable."






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Bone Marrow Stem Cells May Cure Eye Disease

Adult bone marrow stem cells may help cure certain genetic eye diseases, according to University of Cincinnati researchers.

Scientists have completed a study using mice which showed that bone marrow stem cells can switch roles and produce keratocan, a natural protein involved in the growth of the cornea—the transparent, outer layer of the eyeball. This ability of marrow cells to “differentiate” into keratocan-producing cells might provide a means for treating abnormal corneal cell growth in people.

Winston Whei-Yang Kao, professor of ophthalmology, and Hongshan Liu, research scientist in the department of ophthalmology, was to present their findings at the annual meeting of the Association for Research in Vision and Ophthalmology being held in Ft. Lauderdale, Fla., May 9 and10.

In the laboratory, the researchers induced corneal abnormalities that mimicked genetic eye mutations and then injected bone marrow stem cells into the corneas to see if they altered the mutations.

The study showed that after only one week, the abnormal corneas of animal models injected with bone marrow stem cells began to change shape and heal.

“We found that bone marrow stem cells can contribute to the formation of connective tissues,” Kao says. “If we can change the function of non-corneal bone marrow stem cells by introducing them into human corneas, we can possibly repair the loss of visual sharpness caused by mutations.”

Kao and his coworkers are now planning a clinical trial. If the trial succeeds, Kao says, the procedure could help prevent blindness in future generations who suffer from genetic corneal diseases.

He added that cornea transplants have been successful to some degree but do not always eliminate the problem.

”When the donor cells disappear after a few years, the corneal disease often reoccurs,” he says. “However, if we can place the stem cells inside the cornea, they will repair the lost function of the mutated gene, and stem cells can presumably renew themselves and maintain effective treatment longer, if not forever.”

This study was funded by grants from the National Eye Institute, Research to Prevent Blindness, and Ohio Lions Eye Research Foundation.


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Researchers 1st To Map Gene That Regulates Adult Stem Cell Growth

A new discovery in stem cell research may mean big things for cancer patients in the future. Gary Van Zant, Ph.D., and a research team at the University of Kentucky published their findings in Nature Genetics, an international scientific journal.

The researchers genetically mapped a stem cell gene and its protein product, Laxetin, and building on that effort, carried the investigation all the way through to the identification of the gene itself. This is the first time such a complete study on a stem cell gene has been carried out. This particular gene is important because it helps regulate the number of adult stem cells in the body, particularly in bone marrow. Now that it has been identified, researchers hope the gene, along with its protein product Latexin, can be used clinically, such as for ramping up the stem cell count in cancer patients undergoing chemotherapy and bone marrow transplantation.

The researchers agreed that this very process is not only interesting, but important because of its usefulness in a wide variety of future genetics studies.

"We're thinking about cancer in a big way," Van Zant says. "This is a great example of translational research – from the most basic type of genetic research all the way to possible treatments for patients."

One big obstacle chemotherapy patients face is stem cell loss after treatments. This limits the dosage amount and types of chemotherapy that can be given. But if Latexin were used to increase the stem cell count, patients would be able to receive increased doses of chemotherapy and be able to recover more quickly. Increased stem cell counts also would be valuable during bone marrow transplants, where the greatest number of stem cells are desired to help a patient recover from cancer.

Another possible use for Latexin would be to help increase the number of stem cells available in umbilical cord blood, which also is used to transplant healthy stem cells in blood marrow transplants. Currently, stem cell transplants with cord blood can only be used in children because cord blood does not contain enough stem cells for an amount needed to be transplanted into an adult.

The only stem cell population that has been examined for effects of Latexin to date is in bone marrow. Van Zant says it is possible, even probable, that other stem cell populations in tissues such as the liver, skin, pancreas or brain may be similarly affected by Latexin. This could open up new therapeutic strategies such as using stem cells for the treatment of other diseases and conditions such as liver disease, diabetes and central nervous system damage as a result of trauma or stroke.

The researchers also are looking into the possible role the gene plays in transforming healthy stem cells into cancerous ones, such as in leukemia and lymphomas. If the gene does in fact play such a role, it is possible that it also could provide the keys to new therapies.

Van Zant describes his discovery as an elation. He worked on the project for six years with Ying Liang, a former graduate student who is now a postdoctoral fellow at UK. Van Zant says this research and publication of the journal article is the culmination of a difficult but rewarding scientific journey.

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