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July 11, 2011
Volume 89, Number 28
p. 6

Controlling Cell Signaling

Tissue Engineering: Preorganization allows signal-induced changes to occur faster

Stu Borman

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Greet And Meet Binding to surface-immobilized peptide ligands causes TβRI (green) and TβRII (purple) cell-surface receptors to preorganize in just the right way (left) for TGF-β binding (right), thereby facilitating cell signaling Proc. Natl. Acad. Sci. USA
Greet And Meet Binding to surface-immobilized peptide ligands causes TβRI (green) and TβRII (purple) cell-surface receptors to preorganize in just the right way (left) for TGF-β binding (right), thereby facilitating cell signaling

A signaling molecule will readily send its message when it encounters a preorganized array of receptors on a cell’s surface, a new study shows (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.1101454108).

The work is the first time preorganized surfaces have been used to spatially control cell signaling, according to the researchers—grad student Lingyin Li, chemistry and biochemistry professor Laura L. Kiessling, and coworkers at the University of Wisconsin, Madison. Potential applications include creating biological tissues with patterned functionality by causing cells to differentiate into other cell types in specific locations.

Kiessling and coworkers were inspired by the late chemist Donald J. Cram’s concept of “preorganization,” the idea that host-guest interactions are most favorable when host and guest have complementary shapes. They set out to apply the concept to TGF-β, a signaling molecule that plays key roles in development, wound healing, cell differentiation, cancer, inflammation, and other biological processes.

For signaling to occur, TGF-β must land on a cell surface and gather together and bind TβRI and TβRII, receptor dimers required for its activation. Kiessling and coworkers speculated that using peptide ligands to preorganize both receptor dimers in the correct pattern on cell surfaces would facilitate TGF-β-induced signaling.

The strategy worked. When they coat the peptide ligands on slides, epithelial cells bind to the slides, and the ligands preorganize cell-surface TβRI and TβRII. When they then add TGF-β, it binds the receptors, generating signals that cause nearly all the epithelial cells to differentiate to mesenchymal cells within 48 hours. In contrast, far less differentiation occurs on nonpreorganized cell surfaces. Preorganization-induced signaling causes the same changes in gene expression as those caused by unaided signaling.

The peptide ligands do not compete with TGF-β for binding sites on the receptor dimers; they simply arrange the receptor dimers to be ready for TGF-β, as a chef might collect all the ingredients for a recipe in advance. The researchers believe the preorganization approach will also prove applicable to rapidly activating other types of cell-signaling molecules.

“Kiessling and coworkers have achieved a synthetic tour de force here,” comments biophysicist Dennis E. Discher of the University of Pennsylvania, whose areas of specialization include cell adhesion and differentiation. “They have made novel peptides that are intelligently immobilized in clusters to activate a major growth-factor pathway. In showing that thousands of genes are activated by their peptide-coated surfaces in a manner similar to the naturally soluble TGF-β, one can imagine all sorts of new applications such as smart bandages that help close wounds.”

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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