Researchers have discovered that two epigenetic events (removing and adding methyl from DNA) lead to the differentiation of stem cells into muscle cells and thus to the regeneration and healing of muscles after their injury
Epigenetics plays a crucial role in genome activity. Epigenetic markers can silence certain genes and activate others, thus causing or preventing diseases. An example of a central epigenetic marker is methylation - the attachment of a methyl group (a hydrocarbon substance) to the DNA molecule and the expression of unique proteins that block access to the gene. The blocking of the gene silences him and does not allow him to express himself.
Dr. Tal Falik Michaeli is a doctor and researcher at the Oncology Institute at Hadassah Ein Kerem Hospital, who focuses on the field of epigenetics, regenerative medicine and cancer. Her latest research was done with the support of the National Science Foundation, in collaboration with Prof. Yehudit Bergman and Prof. Chaim Sider from the Department of Developmental Biology and Cancer Research at the Faculty of Medicine at the Hebrew University, one of the world's leaders in the field of epigenetics. Their goal was to understand how stem cells, which can differentiate into different cells and thus regenerate and heal damaged tissues and organs, change epigenetically following damage, for example to a muscle. For example, how the methylation that occurs in their DNA due to the damage, which changes the expression of their genes, affects their differentiation into muscle cells.
Says Dr. Falik Michaeli: "We know that after the muscle is injured, its stem cells differentiate into muscle cells and that this process is accompanied by regional epigenetic changes, for example in DNA methylation, that is, in the gene expression control system in the cell. Now we discovered that these changes are necessary for the proper differentiation of the stem cells into muscle cells and thus for the healing of the muscle."
As part of their research, the researchers injured a muscle in one or both legs of mice (perforated the muscles or froze them with liquid nitrogen). After that, the muscle tissues were isolated and tested with molecular methods. Thus they discovered that two epigenetic events took place in different genomic regions in the tissues that led to the differentiation of the stem cells into muscle cells, the regeneration of the muscles and their recovery - demethylation (removing methyl from DNA by enzymes) and de novo methylation (adding methyl by enzymes).
To make sure that these events are the ones that really lead to the differentiation of the stem cells, the researchers also created a model of transgenic mice (genetically engineered) - they damaged the relevant enzymes and thus prevented their stem cells from undergoing demethylation, which impaired their ability to differentiate into muscle cells. In other words, this is how they were able to show that demethylation is necessary for the differentiation of stem cells into muscle cells and muscle healing.
Following on from a previous study - done in collaboration with Dr. Yuval Gialchinsky, an expert in obstetrics and gynecology, in which the researchers demonstrated rapid regeneration of injured muscles in pregnant mice - the researchers performed another experiment. In the course of it, they examined leg muscles of pregnant mice with molecular methods and discovered that the stem cells in them are already in the methylation pattern that leads to the differentiation of stem cells (demethylation and de novo methylation events have occurred). "Apparently during pregnancy, the cells in advance prepare themselves epigenetically for possible damage," explains Dr. Falik Michaeli.
The researchers injured the leg muscles of the pregnant mice and saw that indeed the differentiation of the stem cells into muscle cells in them was faster than in the other mice, which led to the building and rapid recovery of the muscles. A similar pattern was observed in another mouse whose leg muscle the researchers injured; Two months after the leg muscle injury, the stem cells in the other leg muscles were already in the methylation pattern that should lead to their differentiation, and this epigenetic change was maintained long after the injury. According to Dr. Falik Michaeli, "We discovered that the epigenetic system remembers the change that occurred due to the damage. This epigenetic memory allows the muscles to cope much better with the next damage. That is, the epigenetic system causes the body to listen to the environment and change so that it is ready to successfully deal with the next damage."
Dr. Tal Falik Michaeli, 39, married (to an ophthalmologist) + four children (8, 6, 4 and a one and a half month old baby), lives in Jerusalem. She will soon complete a post-doctorate in cancer epigenetics with Prof. Haim Sider and a specialization in oncology and radiotherapy at the Oncology Institute at Hadassah Ein Kerem Hospital (physician-researcher track). At the same time, she serves as the coordinator of the specialization course in medical innovation and entrepreneurship management for medical students and teaches in the Bio Innovation course (the graduation project of the specialization in medical innovation and entrepreneurship management) at the Hebrew University.
likes to travel, read, watch movies, dance and work in the laboratory ("I really like science").