Researchers Demonstrate Key Pathway Linked To Heart Development
By manipulating a critical cell-to-cell signaling pathway,
researchers have successfully increased the number cells required for
the normal development of right-sided structures in the heart,
including the right ventricle.
Penn scientists were able to increase the numbers of a cardiac stem
cell population, called Isl-1 positive cardiac progenitors, in the
developing embryo and in tissue grown in a culture dish by activating
the Wnt pathway. The finding suggests a potential therapeutic
strategy whereby influencing this pathway would be used to generate
specialized heart cells to repair or replace cells damaged by cardiac
disease.
"This is the first evidence that the Wnt signaling pathway plays a
crucial role in the generation of cells that can differentiate into
functioning cardiac structures," said Edward E. Morrisey, PhD,
Associate Professor of Medicine and Cell and Developmental Biology
and the senior author on the paper. "Our studies indicate a direct
link between Wnt and a specific family of progenitor cells that
transform themselves into critical structures in the heart during
development.
Although scientists know that the Isl-1 positive progenitor cells
play an important role in the development of the right side of the
heart including the right ventricle, the molecular pathways
regulating these critical cells are poorly understood. Isl-1
progenitors have been shown to have the capacity of self-renewal and
to differentiate into specialized cells including cardiac myocytes
and smooth muscle cells, thus exhibiting the characteristics of
tissue specific stem cells. Morrisey and his team first demonstrated
that the Wnt signaling pathway is active in Isl-1 progenitors.
The next step taken by the Penn researchers was to increase or
decrease the activity of the Wnt pathway to increase or decrease the
number of Isl-1 progenitors respectively, the first time this has
been shown in a mouse model. This resulted in the loss of the right
ventricle, which Isl-1 progenitors contribute to, whereas the left
ventricle, which Isl-1 progenitors do not contribute towards, was
spared.
The scientists also noticed that in addition to an increase in the
numbers of Isl-1 positive cells, there was also an increase in a
class of growth factors that has been shown to act cooperatively with
Wnt signaling to regulate progenitor cells in other tissues. Having
determined that the class of proteins called Fibroblast Growth
Factors or FGFs worked downstream from Wnt signaling, the Penn
scientists went on to show that at least one of the FGF ligands,
FGF10, known to directly impact the development of the heart, was a
direct target of Wnt signaling.
"Isl-I progenitors are present in the early postnatal heart, but
disappear with progressing age," says Dr. Morrisey. "Given the
extreme rarity of these cells and their ability to act as progenitors
of mature cardiac myocytes, the capacity of Wnt signaling to expand
this population may prove to be useful in future work to harness the
ability of these cells to regenerate damaged cardiac tissue."
By: University Of Pennsylvania Health System on Jul 19 2007 08:02:31
http://www.emaxheal
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