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 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 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.
The authors went on to show that increased proliferation of healthy heart cells was responsible for this change and led to a fully functional heart. Nevertheless, despite normal cardiac function early in life, over 40% of adult mice prematurely developed cardiac pathologies which may indicate a hitherto unsuspected embryological origin for early onset cardiac disease in humans.
"Our findings reveal an impressive regenerative capacity of the fetal 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.
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," Jörg-Detlef Drenckhahn of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch 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.
The researchers include Jorg-Detlef Drenckhahn, Monash University, Melbourne, Australia, University of Adelaide, Adelaide, Australia, Max-Delbruck Center for Molecular Medicine, Berlin, Germany; Quenten P. Schwarz, University of Adelaide, Adelaide, Australia; Stephen Gray, Monash University, Melbourne, Australia; Adrienne Laskowski, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia; Helen Kiriazis, Baker IDI Heart Research and Diabetes Institute, Melbourne, Australia; Ziqiu Ming, Baker IDI Heart Research and Diabetes Institute, Melbourne, Australia; Richard P. Harvey, Victor Chang Cardiac Research Institute, Sydney, Australia; Xiao-Jun Du, Baker IDI Heart Research and Diabetes Institute, Melbourne, Australia; David R. Thorburn, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia, University of Melbourne, Melbourne, Australia; and Timothy C. Cox, Monash University, Melbourne, Australia, University of Adelaide, Adelaide, Australia, University of Washington, Seattle, WA.
Materials provided by Cell Press. Note: Content may be edited for style and length.
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