Monday, 13 October 2008

Embryonic Heart Exhibits Impressive Regenerative Capacity

Embryonic Heart Exhibits Impressive Regenerative Capacity Monday, 13 October 2008 A new study demonstrates that the embryonic mouse heart has an astounding capacity to regenerate, a phenomenon previously observed only in non-mammalian species. The research, published by Cell Press in the October 14th issue of the journal Developmental Cell, describes the previously unrecognized potential of the embryonic heart to replace diseased tissue through compensatory proliferation of healthy cells. Disorders of the mitochondria, a cell structure required for energy production, are one of the leading causes of fatal early onset cardiomyopathies. To investigate how mutations that interfere with mitochondrial function impact the heart during development, Professor Timothy C. Cox from the University of Washington in Seattle and colleagues from Australia, used a heart-specific knockout approach in mice to inactivate a gene crucial for normal mitochondrial function. Their experimental methods established embryonic female mice with mosaic hearts composed of mixed cell populations: half normal and half "diseased" (lacking the gene). However, surprisingly, at birth the diseased cells represented only about 10% of the cardiac tissue. Dr. Jörg-Detlef Drenckhahn, now at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch said: "Hopefully, our results will lead to new therapies in the future. With the right signals, a heart that has been damaged – for example through infarction – might be stimulated to heal itself." 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 foetal 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. This may indicate a hitherto unsuspected embryological origin for early onset cardiac disease in humans. The scientists, therefore, want to inactivate the gene in adult mice as well in order to investigate its influence. "Our findings reveal an impressive regenerative capacity of the foetal heart that can compensate for an effective loss of half of the cardiac tissue," concludes Professor Cox. "To the best of our knowledge, this represents the first in vivo demonstration of selection against diseased tissue during embryonic heart development." The work also suggests that some cell populations within the heart are better able to regenerate than others and that those others are likely to be the source of later pathology. Furthermore, they want to identify the embryonic/foetal 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. Reference: Compensatory growth of healthy cardiac cells in the presence of diseased cells restores tissue homeostasis during heart development Jörg-Detlef Drenckhahn1, Quenten P. Schwarz, Stephen Gray, Adrienne Laskowski, Helen Kiriazis, Ziqiu Ming, Richard P. Harvey, Xiao-Jun Du, David R. Thorburn and Timothy C. Cox Developmental Cell, 15, 521-533, October 14, 2008 See also: Embryonic Stem Cells Repair Congenital Heart Defect CellNEWS - Friday, 12 September 2008 ......... ZenMaster

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