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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St. Jude Psychologist Says Most Children With Cancer Are Well-Adjusted

Children under treatment for cancer are generally emotionally well-adjusted and no more depressed or anxious than other children their age, according to researchers at St. Jude Children’s Research Hospital. In studies of depression, anxiety, posttraumatic stress and quality of life, children with cancer do as well as, and often better than their healthy peers.

“We see them as a flourishing population that has adapted to the stress of having cancer and undergoing treatment,” says Sean Phipps, a member of the St. Jude Division of Behavioral Medicine. “They become quite resilient to the long-and short-term emotional and physical effects of their disease and the treatments.”

The unexpected finding that children with cancer are emotionally resilient is important because of the dramatic improvement in survival rates of pediatric cancers. “There has been a shift in research toward the concerns of long-term survivors of pediatric cancers,” Phipps says. “The ability of these children to cope with the after-effects of cancer is the major issue now. What we are learning from this population might help us learn how to improve the quality of life of children who are not doing so well.”

Phipps is the author of an article on adaptive styles in children with cancer that appears in the advanced online issue of Journal of Pediatric Psychology. The article, based on research done by his group and other research teams around the country, was presented at the conference “Psychosocial and Neurocognitive Consequences of Childhood Cancer: A Symposium in Tribute to Raymond K. Mulhern,” held at St. Jude in September 2006, in honor of the late Raymond Mulhern, a pioneer in psychological research in pediatric oncology at the hospital. The symposium’s presentations will also appear in a special December issue of the journal.

The low level of depression among children with cancer does not reflect a state of “illusory mental health,” Phipps says. That is, these children are not simply clinging to an illusion of mental health by denying distress. Rather, many of them simply have a reduced awareness of emotional distress, and they think of themselves as being well-adjusted and content, a response called a “repressive adaptive style.”

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St. Jude Study Yields Secrets of Chromosome Movement

Investigators at St. Jude Children's Research Hospital have used the lowly yeast to gain insights into how a dividing human cell ensures that an identical set of chromosomes gets passed on to each new daughter cell. Errors in this critical part of cell division can cause one daughter cell to get extra copies of some chromosomes that should have moved into the other daughter cell, or no copies of other chromosomes—a problem that is prevalent in cancer and can cause miscarriages or disease, such as Down syndrome.

St. Jude researchers made their discovery by tracking the activity of a small army of molecules with exotic names like argonaute (Ago1) and dicer; these molecules help maintain a specialized, tightly packaged form of DNA called heterochromatin at the part of the chromosome called the centromere. The investigators also showed the order in which certain critical events occur in setting up and maintaining this heterochromatin. The work is important because it gives scientists insight into how each daughter cell receives the normal number of chromosomes; and it offers important clues to understanding the genetic cause of certain catastrophic diseases. A report on this work appears in the May 25 issue of Molecular Cell.

All of the cell’s DNA is wrapped around a series of structures, called histone octamers, to generate chromatin—much like thread wound around a spool. This chromatin is then further compacted to form the characteristic, thick structures commonly recognized in illustrations and photographs as chromosomes. At the centromere, DNA is packaged into an even more compact and specialized form of chromatin called centromeric heterochromatin.

The centromere is the last point at which the two identical chromosomes are joined before the cell divides. Centromeric heterochromatin helps to yoke together the “sister chromatids” of each chromosome pair as they line up in the center of the dividing cell before separating and moving into their respective daughter cells. When the cell has ensured that it is safe to continue dividing, each sister chromatid moves in opposite directions toward the two new daughter cells that are forming.

“The cell must establish and then maintain centromeric heterochromatin to ensure that each chromosome pair is stable and securely linked together until it’s time to separate,” says Janet Partridge, assistant member of the St. Jude Department of Biochemistry. “Otherwise, the chromosome pairs would drift apart and leave daughter cells with too many or too few chromosomes.” Partridge is the report’s senior author.

The St. Jude team studied combinations of molecules in yeast called the RITS and RDRC complexes, which together with an enzyme called Clr4 (Suv39 in humans), establish and maintain centromeric heterochromatin in the yeast cell during a carefully choreographed series of steps.


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