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Sealing a Cell's Fate

2/4/2003 -- A collaboration of scientists,
led by Dr. Janet Rossant at the University of Toronto and The
Samuel Lunenfeld Research Institute at Mount Sinai Hospital,
has identified two genes whose combined expression drives the
development of the blood and blood vessels in early
embryogenesis. This discovery lends new insight into the
molecular cues that direct blood and vascular development -- a
crucial event in both normal and pathological processes, like
tumor angiogenesis. Their results were published in Genes &
Development.

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Dr. Rossant and colleagues have discovered that
the proteins encoded by two genes, called Flk1 and Tal1, coax
embryonic progenitor cells to become either cells that compose
the blood (hematopoietic cells), line the blood vessels
(endothelial cells), or help support the blood vessel walls
(smooth muscle cells). While it has been hypothesized that
endothelial and hematopoietic cells are derived from a common
progenitor cell, called the hemangioblast, Dr. Rossant and
colleagues now show that the co-expression of Flk1 and Tal1 in
the hemangioblast is necessary for normal endothelial,
hematopoietic, and smooth muscle cell specification.

"We are interested in trying to understand the
relationships between cells of the blood, and the cells lining
the blood vessels in which they are transported. Surprisingly,
our studies and those of others suggest that, at least in the
early embryo, these two cells come from a common progenitor,
the hemangioblast. What is more, the same progenitor can give
rise to the smooth muscle cells of the vessel walls," explains
Dr. Rossant

Flk1 encodes a cell surface receptor for the
vascular endothelial growth factor (VEGF), a crucial factor in
angiogenesis. Transgenic mice lacking Flk1 fail to form
endothelial and hematopoietic cells, and also fail to express
the transcription factor Tal1. To test the effect of Tal1 on
hemangioblast development, Dr. Rossant and colleagues
reintroduced Tal1 into Flk1-deficient mouse embryos and
embryonic stem (ES) cells.

These Tal1-expressing, Flk1-deficient mouse
embryos still died in utero, but the development of
endothelial and hematopoietic cells was improved. More marked,
though, was the ability of Tal1-expressing, Flk1-deficient ES
cells to differentiate into hematopoietic cells at levels
comparable to that of ES cells missing only one copy of Flk1
(Flk1-heterozygous ES cells). The researchers also expressed
additional Tal1 in Flk1-heterozygous ES cells, and found that
this enhanced expression of Tal1 both augmented the cells'
hematopoietic potential and enabled the cells to differentiate
into smooth muscle cells.

Taken together, these findings provide further
support for the existence of a common hemangioblast progenitor
cell, in which the dual expression of Flk1 and Tal1 steer
cells into a path of either endothelial, hematopoietic, or
smooth muscle cell fate.

"Using mouse embryonic stem cells we have been
able to manipulate the proportions of the three different cell
types arising from the hemangioblast by altering expression of
a signaling pathway and one of its downstream effector
molecules. These kinds of studies will help us understand how
to manipulate human stem cells for therapeutic uses in
vascular damage and disease," states Dr. Rossant.

Source: Cold Spring Harbor Laboratory

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