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26 | APRIL 15, 2017 | GENengnews.com | Genetic Engineering & Biotechnology News influence tissue repair and regeneration operate by triggering epigenetic changes that determine the activities of cells that are responsible for wound healing," explains Derek Mann, Ph.D., professor of hepatology at Newcastle University. "As an example, alcohol can induce epigenetic changes in wound-healing cells in the liver that promote excessive scar formation. "In addition, the process of generating wound-healing myofibroblasts is under the control of epigenetic mecha- nisms that determine the phenotype, activities, and fate of these cells." Dr. Mann and his team have a focus on developing new therapies for liver fibrosis. They demonstrated that epigen- etic regulator proteins, such as MECP2, EZH2, and ASH1, change gene expression at the chromatin level and promote fibrosis by stimulating the myofibroblast cells to produce col- lagen. If these proteins are "turned off," then it is possible to stop progression of fibrosis in the diseased liver. At present, the main method of confirming liver fibrosis is through invasive liver biopsy. However, Dr. Mann and col- leagues showed that quantification of DNA methylation in circulating cell-free DNA can provide a surrogate biomarker for liver fibrosis. "We are anticipating that our continuing work on epi- genetics in fibrosis will lead to the development of new bio- markers that are diagnostic and prognostic for fibrosis pro- gression in patients with chronic liver disease," says Dr. Mann. Elisabeth Zeisberg, M.D., Ph.D., a group leader at the Medical University of Göttingen, also works on the epi- genetics of tissue fibrosis. "Just like in cancer," she says, "where tumor-suppressor genes have been studied for de- cades, we now understand that there are also 'fibrosis-sup- pressor genes' which can be silenced or reactivated by epi- genetic mechanisms." Dr. Zeisberg and co-researchers have identified a gene called RASAL1, which when silenced through epigenetic control contributes to kidney, heart, and liver fibrosis. They found that reactivating this gene can stop the fibrotic process. Repurposing of drugs already approved for one condition to treat another is being investigated in a number of clinical areas. Dr. Zeisberg and her team discovered that the antihy- pertensive drug hydralazine, used to lower blood pressure in pregnant women, can improve outcomes in experimental models of kidney and heart fibrosis by activating genes in- volved with fibrosis. "Due to its safeness, it provides an attractive opportunity for clinical translation," states Dr. Zeisberg. "We are current- ly planning a prospective clinical trial to test its effectiveness in treating heart fibrosis." Both Dr. Mann and Dr. Zeisberg are searching for DNA methylation-based biomarkers that can help predict who will develop fibrosis, as well as indicate a patient's prognosis once the condition is detected. "This is important since fibrosis is a silent pathology that often only presents at a late stage where treatments may not be possible," insists Dr. Mann. "It would provide greatly improved personal clinical management for patients and en- able selection of patients for future clinical trials with anti- fibrotic drugs." Dr. Zeisberg explains that her team is investigating the potential for developing biomarker-stratified, targeted thera- pies. "Our main focus," she elaborates, "is to develop Cas9- directed enzymes to specifically de-methylate select genes." Importance of Mechanics and Positioning While epigenetic changes tend to occur in response to bio- chemical triggers, a healthy physical environment is equally important for healthy tissue repair and regeneration. "People have learned in the last 20 years that cells do much more than just respond to biochemical factors. In- stead, it is well documented today that the way in which cells anchor themselves to their surroundings and what they feel when they pull on those anchors has an impact on gene ex- pression," comments Viola Vogel, Ph.D., professor and dep- uty chair of the department of health science and technology, and head of the Laboratory of Applied Mechanobiology at ETH Zürich. She believes that a lot of tissue-engineering research has been simplistic and has yet to adequately address the forces by which cells stretch the surrounding tissue fibers, forces that alter the biochemical display of these fibers, which then in a feedback loop alter cell and tissue functions. However, "the feedback between engineers, biologists, and the medical community is steadily increasing. Engineers learn from biologists how to better mimic aspects of real tissue, and biologists learn from engineers how to prepare better 3D model systems to study cell function in complex environments," she explains. "There are no good tools to map localized forces in real tissues at high resolution; for example, to find out how much force cells generate in healthy versus diseased tissues, and how much they stretch the fibers that surround them," notes Dr. Vogel. "Currently, we are trying to develop such probes." Yuval Rinkevich, Ph.D., head of a laboratory at the Helmholtz Zentrum München, also believes it is important to reflect the natural tissue environment as closely as pos- sible: "We know a lot of what is happening in cell culture doesn't really reflect what's happening in vivo, and so we try to keep it as close as possible to the native settings where the cells operate." Dr. Rinkevich and colleagues are using dermal fibroblast lineages to study a number of cell types involved in wound A Better Environment for Tissue Repair See Tissue Repair on page 28 Researchers at the Medical University of Göttingen have identified an epigenetic mechanism, transcriptional suppression of RASAL1 through aberrant promoter methylation, that contributes to cardiac fibrosis. The aberrant methylation can be reversed through Tet3-mediated hydroxymethylation. Here, confocal microscopy shows the expression pattern of DNA methyltransferase (DNMT) and Tet3 (TET) in cardiac endothelial cells. The freshwater polyp Hydra, a champion of regeneration,is being studied by scientists at the University of Geneva. They recently found that in the Hydra, cells of the epithelial type modify their genetic program by overexpressing a series of genes, including genes that are involved in diverse nervous functions. Translational Medicine Feature Continued from page 1 We are still in the relatively early stages of the tissue engineering revolution.