Repair in the Developing Heart

For the heart to be able to beat, it needs energy. If during heart development energy
production in the heart cells is disturbed, then the embryo will actually die
of heart dysfunction. But if only a subset 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 functional.

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 one 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 transcribed, either healthy or diseased heart
cells emerge. “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, their
contribution is large enough to allow the heart of the newborn mouse to beat
normally. “But even for a short period after birth, the heart might be 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 heart failure 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
on postnatal cardiac function.

Furthermore,
they want to identify the embryonic/fetal signaling pathways that stimulate healthy cells to
proliferate and inhibit diseased cells. The scientists hope that, in the
future, these signaling molecules may help stimulate the body’s own repair mechanisms of the heart, for
example after a heart attack  or in the
case of heart failure.

In 2007
Dr. Drenckhahn received the Oskar Lapp Prize for his research on the repair of
the fetal heart.