Dr. Jörg-Detlef Drenckhahn of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany and colleagues from Australia were able to demonstrate in female mice that the healthy cells of the heart divide more frequently and thus displace the damaged tissue. "Hopefully, our results will lead to new therapies in the future," he said. (Developmental Cell, 15, 521-533, October 14, 2008)*.
For the heart to be able to beat, it needs energy. If the energy production in the heart cells is disturbed, then the embryo will actually die of heart dysfunction. But if only a portion of the cells is affected, this is not the case: With the aid of the remaining healthy cells, the embryo manages to regenerate the heart.
The scientists switched off a gene (Holocytochrome C synthase, abbreviated Hccs) in the developing hearts of mice - a gene that is essential for energy production. Results showed that the embryos died when all cells in the heart were affected by the defective energy production. However, the animals that still had some healthy myocardial cells survived, and at the time of birth they had a heart that was fully able to function.
The gene Hccs is located on one of the sex chromosomes, the X chromosome. In contrast to male animals who have only one X chromosome, females have two X chromosomes. Some of the altered female mice have an X chromosome with the defective Hccs gene and one with the intact Hccs gene. However, in the cells of the female animals, only one X chromosome is active. Depending on which one is expressed, either healthy or diseased heart cells develop. "At this point in time, the heart of the mice is like a mosaic," Dr. Drenckhahn said. "Half of the cells are healthy, the other half not."
Up until birth, the fetal heart manages to improve the ratio of healthy cells to defective cells from the original 50:50 ratio. The defective cells then only comprise ten percent of the entire heart volume. That is possible because the healthy myocardial cells divide much more frequently than the defective cells. Their percentage in the heart increases so that, at the time of birth, the ratio is large enough to allow the heart of the newborn mouse to beat normally. "But even for a while after birth, the heart is capable of compensatory growth of healthy cardiac cells," Dr. Drenckhahn explained.
Later the heart loses this ability. Thus, after approximately one year, some of the mice (13 percent) died of myocardial insufficiency and almost half developed arrhythmia. Why only some of the mice develop heart problems is still unclear. The scientists, therefore, want to inactivate the gene in adult mice as well in order to investigate its influence.
Furthermore, they want to identify the embryonic/fetal signal substances that stimulate healthy cells to proliferate and inhibit diseased cells. The scientists hope that, in the future, these signal substances may help stimulate the body's own repair mechanisms of the heart, for example after a heart attack or in the case of heart insufficiency.
In 2007 Dr. Drenckhahn received the Oskar Lapp Prize for his research on the repair of the fetal heart.
*Compensatory growth of healthy cardiac cells in the presence of diseased cells restores tissue homeostasis during heart development
Jörg-Detlef Drenckhahn1,2,3, Quenten P. Schwarz2,9, Stephen Gray1, Adrienne Laskowski4, Helen Kiriazis5, Ziqiu Ming5, Richard P. Harvey6, Xiao-Jun Du5, David R. Thorburn4,7 and Timothy C. Cox1,2,81Department of Anatomy & Developmental Biology, Monash University, Wellington Road, Clayton VIC 3800, Melbourne, Australia
8Division of Craniofacial Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USABarbara Bachtler
Barbara Bachtler | Max-Delbrück-Centrum
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