Developmental biologists have debated the original source blood cells in adult mammals for over thirty years. Now, a team led by Igor Samokhvalov at the RIKEN Center for Developmental Biology, Kobe, has developed a cell tracing method that unambiguously identifies the yolk sac—an extra-embryonic structure—as a source of blood cells in both the embryo and, later, the adult.
The yolk sac, which provides the developing embryo with nutrients, is the first extra-embryonic structure to form during embryogenesis. This structure is also the first place of embryonic blood cell formation (hematopoiesis). A central question in developmental biology about hematopoiesis is the role—if any—the yolk sac-derived blood cells play in the development of adult blood cells.
“The origin of [the] hematopoietic [blood] system was always obscure and controversial; this was the reason I became interested in this area of hematology,” says Samokhvalov.
To resolve the controversy, the team labored for two years to develop a cell tracing method to follow yolk sac-derived blood cells through later stages of embryonic development1. The ability to study this development non-invasively through time was critical, says Samokhvalov, because removing cells from tissue introduces stresses that can lead to an inaccurate picture of actual embryonic processes.
The method consists of replacing of one copy of a gene called Runx1, which is essential for blood development, with another gene that produces a protein creating ‘tags’ in the cells and all their progeny. The ‘new’ gene is turned on at the same time Runx1 normally is—at a mere 7.5 days after embryonic development begins.
Tagging the earliest Runx1-expressing yolk sac cells at day 7.5 of development allowed the team to follow these cells’ progeny when they’re incorporated into blood vessel walls (Fig. 1 - Click on link below), and evaluate their long-term contribution to the adult blood system.
So clear were the results, remarks Samokhvalov, that “our work showed direct contribution of [the] yolk sac to adult haematopoiesis”. Indeed, the team’s direct and carefully designed cell tracing methodology eliminated ambiguities that could lead to alternative interpretations.
This work settles the long-standing controversy, marking an important step forward in developmental biology. However, the team’s data do not rule out the possibility of an additional source of haematopoietic stem cells in the embryo.
Samokhvalov’s future plans include determining more precisely the extent of the yolk sac’s participation in adult blood development, and whether another source of haematopoietic stem cells occurs in the embryo itself.
Reference
1. Samokhvalov, I.M., Samokhvalova, N.I. & Nishikawa, S. Cell tracing shows the contribution of the yolk sac to adult haematopoesis. Nature 446, 1056–1061 (2007).
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Saeko Okada
Riken Research
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