Cardiac development out of control: Absence of the transcription factor Ajuba during cardiac development, as is the case in the right-hand photo due to genetic intervention, disrupts development of the heart in the fish embryo. In addition to an increased number of cardiac muscle cells (green with red-stained nuclei), the heart is additionally deformed during development. Image: Max Planck Institute for Heart and Lung Research |
It
is not unusual for babies to be born with congenital heart defects.
This is because the development of the heart in the embryo is a process
which is not only extremely complex, but also error-prone. Scientists
from the Max Planck Institute for Heart and Lung Research in Bad Nauheim
have now identified a key molecule that plays a central role in
regulating the function of stem cells in the heart. As a result, not
only could congenital heart defects be avoided in future, but new ways
of stimulating the regeneration of damaged hearts in adults may be
opened up.
It’s
a long road from a cluster of cells to a finished heart. Cell division
transforms what starts out as a collection of only a few cardiac stem
cells into an ever-larger structure from which the various parts of the
heart, such as ventricles, atria, valves and coronary vessels, develop.
This involves the stem and precursor cells undergoing a complex process
which, in addition to tightly regulated cell division, also includes
cell migration, differentiation and specialisation. Once the heart is
complete, the stem cells are finally switched off.
Scientists
from the Max Planck Institute for Heart and Lung Research in Bad
Nauheim have now discovered how major parts of this development process
are regulated. Their search initially focused on finding binding
partners for transcription factor Isl1. Isl1 is characteristic of a
specific group of cardiac stem cells which are consequently also known
as Isl1+ cells. During their search, the researchers came across Ajuba, a
transcription factor from the group of LIM proteins.
“We
then took a closer a look at the interaction between these two
molecules and came to the conclusion that Ajuba must be an important
switch”, says Gergana Dobreva, head of the “Origin of Cardiac Cell
Lineages” Research Group at the Bad Nauheim-based Max Planck Institute.
Using
an animal model, the scientists then investigated the effects of a
defective switch on cardiac development. Embryonic development can be
investigated particularly effectively in the zebrafish. The Bad
Nauheim-based researchers therefore produced a genetically modified fish
that lacked a functioning Ajuba protein. Cardiac development in these
fishes was in fact severely disrupted. In addition to deformation of the
heart, caused by twisting of the cardiac axis, what particularly struck
the researchers was a difference in size in comparison with control
animals.
“In
almost all the investigated fish we observed a dramatic enlargement of
the heart. If Ajuba is absent, there is clearly no other switch that
finally silences the Isl1-controlled part of cardiac development”, says
Dobreva.
Further
investigations revealed that the enlargement of the heart is in fact
attributable to a greatly increased number of cardiac muscle cells. The
reason for this was in turn that the number of Isl1+ cells, i.e. the
cardiac muscle precursor cells, was distinctly raised right from an
early phase of development. Ajuba is a decisive factor in controlling
stem cell activity: it binds to Isl1 molecules, thus blocking their
stimulant effect.
The results from the study could have potential future applications.
“Once
we understand how cardiac development is regulated, we will also be
more familiar with the causes of congenital heart defects and will
consequently be able to consider therapeutic approaches,” comments
Dobreva. Damaged adult hearts can also be repaired in this way:
“One
possibility would be to optimise the production of replacement cells
from embryonic or artificially produced stem cells in the laboratory.
Silencing Ajuba in these cells might enhance their development into
functional cardiac muscle cells. Sufficient replacement cells for
treating patients could be cultured in this way.”
Another
possibility is to stimulate stem cell activity by silencing Ajuba in
the damaged heart and so cause the heart to regenerate itself. Further
studies are now set to investigate how feasible this might be.
