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Spotlight on UCSC stem cell scholar Hema Vayadanathan
Thursday, December 6, 2007
Written by Branwyn Wagman
The UCSC Training Program in Systems Biology of Stem Cells is sponsored by the California Institute for Regenerative Medicine (CIRM), established in early 2005 with the passage of Proposition 71, the California Stem Cell Research and Cures Initiative. Hema Vayadanathan is among the first set of scholars chosen for the UCSC program in July 2006. This story is one of a series of spotlights on the research conducted by these scholars. The advent of the UCSC stem cell training program offered a new research direction for Hema Vayadanathan, a postdoctoral scholar in the laboratory of molecular, cell, and developmental biologist David Feldheim. The Feldheim lab specializes in the role of a family of molecules called ephrins in brain development. “At the same time the opportunity to apply for this fellowship came, some pretty high impact papers came out suggesting that ephrins are involved in neural stem cell proliferation and maintenance of the stem cell niche. I was already looking at ephrin signaling in tissue culture systems, so it was a natural lead-in to see how what we already knew could lead to understanding stem cell biology.” “The training grant has opened a whole new field that I wasn’t even thinking about—a specialized field that takes time and money to start,” she said. “Having the training grant has helped the laboratory feel braver about venturing into this new realm of research. It has been a morale-booster.” Ephrins consist of the receptor molecules called Eph and their related ligands, ephrins, known collectively as Eph/Efn. When receptor and ligand fit together, they can influence cell processes. “Both molecules are capable of signaling into cells to cause growth, death, proliferation, migration, and adhesion,” said Vayadanathan. “They are so multifaceted.” Ephrins play important roles in the development of blood vessels in nerve tissue and in guiding neural axons. “These are big-scale developmental processes,” Vayadanathan said. Vayadanathan wonders if Eph/Efn signaling has anything to do with cell fate choice. “Does it influence a stem cell to stay a stem cell—which is important, because you have to have a basal stem cell population present—or does it influence the stem cell to differentiate?” Stem cells reside in their niche, where they are maintained by proliferation and from which they differentiate and migrate out. Signals from receptors or ligands might shift the balance between maintenance and differentiation one way or another, affecting the cells’ fate choice. If the stem cells proliferate too much, they become cancerous, or they could die or differentiate into other types of cells. Seeking to better understand how Eph/Efn affects stem cells in the brain, Vayadanathan first turned to the scientific literature. Since she did not find much reliable literature to answer this question, she is investigating the question first by looking at RNA expression profiles of 10 different Eph receptors and 5 different ephrin ligands. Then she will investigate how these proteins are actually expressed, using western blots and immunofluorescence methods. The Feldheim lab already has a considerable understanding of how Eph/Efn works in the brain and has developed a technique of activating either the receptor or the ligand by providing the correct soluble binding partner. “We are trying to recreate in a dish what might happen inside complex tissue. Once we understand it in a simplified system, it will be easier to try to understand what’s happening in complex tissue, such as mouse embryonic stem cells.” She is already finding variation in the amount of Eph/Efn’s expressed in embryonic stem cells. Once the stem cells have differentiated into other types of neural cells, Eph/Efn’s don’t seem to be present in high levels. “There’s an inkling of a possibility that signaling the receptors—forward signaling—has a different effect from signaling the ligands—reverse signaling.” Forward signaling occurs when the ephrin ligand binds to an Eph receptor attached to a cell’s membrane, thereby signaling into the cell. Reverse signaling occurs when the ligand remains attached to the membrane of the cell it came from and then happens to bind to an Eph receptor on another cell. The membrane-bound ephrin can influence the cell it is bound to. This is usually not the case, though, as the ligand tends to be free-floating. Vayadanathan aims to build the complete signaling story. “Seeing modulatory effects on cell fate, which differs based on forward or reverse signaling, will impact how we can use these molecules to direct cell fate choices.” She has made progress toward this aim, “We are beginning to see differences in neural fate—the cell populations seem to be responding to the presence of Eph/Efn.” This knowledge will help researchers tinker with the fate of stem cells, learning how to preserve stem cells in the laboratory so that they do not differentiate and then control their differentiation. She likes the idea of contributing basic methodological advances such as this that will help stem cell research, “This is still not easily done in stem cells.” “This would be an important technique,” Vayadanathan said. “Finding out how altering Eph/Efn’s affects embryonic stem cell maintenance would be a helpful methodological advance, especially when moving into human embryonic stem cells. If Eph/Efn’s influence stem cell maintenance and differentiation, it will make researchers’ lives easier. What if adding just one Efn gives you a large number of neural cells from a small number of stem cells? This might give us a handle on how we might direct the differentiation.” Beyond advancing research methodology, this project has potential medical applications. “Long-term, if we were able to control differentiating, it could affect how these stem cells differentiate in neural transplants.” Understanding the molecular mechanisms regulating neural stem cell fate could facilitate the development of targeted therapies for the treatment of neurodegenerative diseases, spinal cord injuries and trauma, and cancer. The next step will be to see what happens in “knockout” mice that are genetically altered to lack various ephrins and Eph’s. “Now with our new transgenic facility, we can derive knockout mouse embryonic stem cells.” This helps understand what not having a particular Eph or ephrin does in the organism. She will be able to build on and contribute to the extensive base of knowledge the Feldheim lab has developed regarding the effects of Ephs and ephrins in mouse models. Having Vayadanathan conducting stem cell research in the Feldheim lab led to another grant from the CIRM for human embryonic stem cell research. “It was a confidence-booster that is important to a small lab.” As a part of the fellowship, Vayadanathan participated in the UCSC stem cell training program. She has taken all of the courses offered so far and helped coordinate and teach Feldheim’s stem cell lab course. Last fall, she attended a human embryonic stem cells training course offered by the NIH in Orange County. It was ten days learning about culturing, handling, and manipulating human embryonic stem cells to prepare for setting up cell lines in the Feldheim laboratory. “It takes a lot of commitment to look into stem cell systems, but the rewards are so great. We would be remiss not to even try,” said Vayadanathan. And UCSC turns out to be a great place to do such research, with state of the art stem cell facilities already available on campus. “With this smaller environment, we can be productive in a shorter period of time.”
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