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Novel Method Developed to Study Blood Vessels in Disease State
volume 6 | issue 9
September 2007Pages: 1343 - 1344
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Scientists have developed a new method of capturing a complete genome-wide screening of blood vessel cells in their actual disease state, advancing the potential for genetic research on the cells responsible for delivering nourishment that can both fortify a cancer tumor or accelerate wound healing.
The method is not just a bonus for translational research, but also has made it possible to determine that genes long associated only with cancer are also expressed in chronic wounds.
The team of scientists, based at Ohio State University Medical Center, is using laser capture microdissection to pluck a single cell from human wound samples as part of a major research initiative looking for the genetics behind wound-healing activity.
They published a description of the research method in the Proceedings of the National Academy of Sciences, scheduled for early edition online publication on Aug. 27.
"We have enabled the capture of a genome-wide screening of blood vessels regardless of disease," said Dr. Chandan Sen, executive director of Ohio State's Comprehensive Wound Center and senior author of the paper. "It's a big lift for our ability to perform translational research at the level of molecular biology resolution."
The method is superior to previous methods of cell biology research because it allows scientists to study a single type of cell in an actual diseased state, said Sen, also professor and vice chair of surgery and deputy director of Ohio State's Davis Heart and Lung Research Institute. Standard research methods, such as examining cells in the lining of vessel walls, are conducted by cell culture, meaning the cells are removed from their disease environment and placed in dish. And biopsy tissue studies include fat and muscle cells in addition to diseased vascular cells, preventing the ability to examine uniform cell samples across multiple biopsies.
Blood vessels are critical components of multiple diseases, so their quick identification and analysis at the cellular level has broad implications. "The main strategies of limiting cancer are to stop the vasculature of a tumor. So if you know the biology of the blood vessel feeding the tumor, you can halt that action and the tumor can no longer grow," Sen said. "In the case of chronic wounds, the tissue can grow only if blood vessels bring food - blood and oxygen - to fuel the healing process.
"In both diseases, you need a clear understanding of vascular biology."
The cells screened for the study of the genetics of wound healing are supplied by the world's only wound tissue bank, which currently holds 500 samples collected from seven U.S. centers affiliated with National Healing Corp. Ohio State's Comprehensive Wound Center has a partnership with National Healing Corp., a private Florida company that manages 20 percent of the nation's wound-healing centers
"Traditionally, in wound healing, there has been no way to tell what's going on in the wound except by visualization and what a biopsy says - whether it's infected or cancerous. We're advancing the depth and level of this knowledge in our investigation," said Dr. Gayle Gordillo, director of the plastic surgery research lab at Ohio State's Medical Center and co-author of the paper. Gordillo also is principal investigator of the wound-healing study, informally called the "Gene Screen."
This analysis is designed to demonstrate which genes predict healing and which genes are expressed in wounds that are chronic and predict a failure to heal. The researchers are taking biopsies from clinic patients with both healing and non-healing wounds and using the laser capture microdissection to study a homogeneous cell population and run the full genome screen.
The laser capture technology allows the scientists to zero in on the microvessels, which are expected to sprout when tissue is healing. If the microvessels in chronic wound samples are not sprouting, the researchers can then turn to endothelial cells - in the lining of blood vessel walls - to see if there is a genetic basis in those cells for why wounds do or don't heal.
A third team leader, Dr. Sashwati Roy, assistant professor of surgery and first author of the PNAS paper, is a molecular biologist whose expertise lies in sorting out the meaning of the data collected from the genes and identifying candidate genes involved in healing.
"One little genetic mutation can affect a person's response to medications. The laser capture microdissection is really precise and gives us all the material we need from a single cell," Roy said.
The paper also detailed early findings in the "Gene Screen" that show the striking contrast between blood vessels collected from intact skin and wound-edge tissue. The scientists identified a total of 54 up-regulated genes and 24 down-regulated genes in their comparison. The most notable finding was the prominence in wound-site blood vessels of the protein periostin, previously associated with cancer because of its contribution to tumor growth.
"The basic assumption has been that the blood vessels in intact skin and wounds are the same. What we're seeing instead is that genes thought to be uniquely expressed in cancer are also expressed in wounds. None of these genes has been studied in wound healing," Sen said. "So ultimately, this cell biology research technique is one that generates new hypotheses rather than just testing them. It's a highlight for patient-based research."
This work was supported by the National Institutes of Health, the National Science Foundation and Ohio State's General Clinical Research Center. Additional Ohio State co-authors are Darshan Patel, Savita Khanna, Sabyasachi Biswas and Avner Friedman.
For more information ontact: Emily Caldwell, Medical Center Communications, 614-293-3737 or emily.caldwell@osumc.edu