Wnt signalling stimulates the beginnings of gastrulation
Left to their own devices, cultured pluripotent stem cells clump together. A hotchpotch of differentiated cells forms within these so-called 'embryoid bodies', and in fact, the formation of embryoid bodies is a preliminary assay of good quality in embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. Researchers led by Roel Nusse at Stanford School of Medicine in California have now observed something surprising in these much studied structures: they spontaneously begin a process called gastrulation, the cell movements that occur in mammalian embryos after implantation and which result in the formation of the three germ layers of the animal body.
“It is not a surprise to find that gastrulation can happen in embryoid bodies but the use of fluorescence-based tools allows the visualization of the gastrulation phenomenon occurring in vitro which mimics rather faithfully the in vivo process,” says Luc Leyns, who studies Wnt signaling and embryonic patterning at Vrije Universiteit Brussels in Belgium. Embryoid bodies generally contain single clusters of, say, neural or mesodermal cells, he says. “These results suggests that a coordinating mechanism exists but this one is still to be identified.”
The 'gastrulation' process in the embryoid bodies depends on a ubiquitous signalling protein known as Wnt, and though Wnt is known to be essential for gastrulation in mammalian embryos, no one had looked for it in embryoid bodies, says Nusse. His lab members Derk ten Berge and Wouter Koole used a series of established Wnt reporters to visualize Wnt signalling in embryoid bodies formed from mouse ES cells, and found a surprising level of organization1. The embryoid bodies began to develop regions that resembled the primitive streak, the area through which cells travel to form the mesoderm. This created a polarization within the embryoid bodies, and the formation of the primitive streak-like region depended on local activation of the Wnt-pathway. Once Wnt signaling starts in the embryoid body, it is self-reinforcing. Cells within this region underwent a switch known as the epithelial-to-mesenchymal transition and began to differentiated into mesoendodermal progenitors.
Wnt influences the differentiation in all sorts of cell types in many different ways, and the fact that Wnt signalling starts spontaneously in embryoid bodies suggests a range of techniques that might be used to control the differentiation of cultured stem cells, says Nusse. “If you can mimic that [guided differentiation] in cell culture, that is a step toward instructing ES cells to become committed to other fates.”
What's unclear is what establishes Wnt signalling in the first place: some constituents of serum-based media seem to trigger it, so differentiation protocols that use media without serum might be more predictable, says Nusse.
Ethical oversight committees at universities do not allow researchers to perform experiments on human embryos or embryo-like entities after the first appearance of the primitive streak, which occurs at thebeginning of gastrulation. Nusse performed his experiments on mouse embryoid bodies, but he doubts that his findings will prevent work in human cells because embryoid bodies show only the very beginning of gastrulation. Nonetheless, he says, “What happens in an embryoid body is more like what happens in an embryo than previously appreciated.”
ten Berge, D. et al. Wnt signaling mediates self-organization and axis formation in embryoid bodies. Cell Stem Cell 3, 508–518 (2008).
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Baker, M. Embryoid bodies get organized. Nat Rep Stem Cells (2008). https://doi.org/10.1038/stemcells.2008.146