Technology Feature

Nature 451, 856 (14 February 2008) | doi:10.1038/451856a; Published online 13 February 2008

Stem Cells: Beyond the flat world

In culture, stem cells rely on signals to differentiate to other cell lineages. Although certain growth factors are known to promote some differentiation programmes, it is now becoming clear that physical interactions between cells and mechanical sensing may also help to promote differentiation. So researchers are developing a variety of three-dimensional (3D) matrices for stem-cell differentiation.

In 2006, Dennis Discher of the University of Pennsylvania in Philadelphia, and his colleagues, demonstrated the potential of the matrix alone to promote differentiation. "The idea was to use synthetic gels with a collagen monolayer to mimic the elasticities of certain tissues and see how the cells respond," says Discher. The work was done under constant serum conditions, without any discriminating soluble factors or growth factors that might promote differentiation in one direction or another. The results showed that by simply varying the elasticity of the matrix, the attached mesenchymal stem cells could undergo either neurogenesis, myogeneis or osteogenesis. They went on to show that once the cells adhere, they begin setting up the stress fibres that actively pull on the adhesions and on the matrix outside. "We showed that the cells feel the matrix and respond to it," says Discher.

Stem CellsBeyond the flat world


Three-dimensional matrices can promote cell differentiation.

Stefan Przyborski is the founder of Reinnervate in Durham, UK, the developer of a new scaffold for routine 3D cell culture. "We create ways of making the in vitro environment a more realistic environment for cell growth," he says. Reinnervate's scaffold is unique, but might seem familiar to biologists who have performed cell culture. "We created a scaffold made of polystyrene, the same material that people currently grow their cells on." This is important because researchers know how cells respond to this material in two-dimensional applications. But he also notes that this 3D environment enhances differentiation when compared with cells cultured on two-dimensional plates.

Invitrogen of Carlsbad, California has developed Algimatrix, an inert 3D scaffold made of alginate. "The idea behind Algimatrix is that it provides a framework for cells to reside in that will enable formation of spheroidal structures in a controlled manner," says Mark Powers, a director at Invitrogen. Powers says that when embryonic stem cells form embryoid bodies, they can aggregate into very large structures where the cells on the inside can be oxygen or nutrient limited. But with Algimatrix the aggregates grow to a consistent size and not beyond the size of the pores provided by the scaffold. And since it is an inert scaffold, it actually promotes cell interactions. "A scaffold such as Algimatrix would allow a researcher to culture cells in 3D aggregates to promote differentiation."

It is becoming clear that mechanical interaction has a role in cell differentiation. "What we are really describing is a sense of touch — the cells have no eyes or ears, so they use this sense of touch to tell where they are — this is all part of sensing and responding to the environment," says Discher.



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