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.
Journal
Genes & Development