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Biological Chemistry

Sugar Mimic Helps Embryonic Stem Cells Develop Toward Nerve Cells

Chemical Biology: Molecule mimics proteoglycans that play a role in stem cell differentiation

by Melissae Fellet
July 28, 2014

Cellular Switch
Micrographs of mouse embryonic stem cells and a neural rosette.
Credit: J. Am. Chem. Soc.
Researchers added a fluorescently labeled proteoglycan mimic to mouse embryonic stem cells (left). The mimic, along with fibroblast growth factor 2, triggered the cells to differentiate into a neural rosette (right), a structure that contains precursors to nerve cells.

Long chains of sugars dangle from proteins on the surface of embryonic stem cells and play an important role in how the cells develop into specific cell types. Researchers have now synthesized a molecular mimic of these sugar-decorated proteins that helps direct mouse embryonic stem cells down the path toward nerve cells (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja505012a). The researchers hope others can easily adopt the method to explore how these cell surface sugars influence stem cell differentiation.

As an embryo develops, different growth factors flood the area around stem cells, serving as cues for the cells to differentiate into specific tissue types. These growth factors bind to cell surface receptors that then trigger internal biochemical pathways responsible for setting the stem cell’s fate. Scientists want to mimic this process to control how stem cells differentiate in the lab. However, some growth factors, such as fibroblast growth factor 2 (FGF2), don’t simply bind to a surface receptor. To trigger differentiation, these growth factors also must bind to sugars attached to proteins called proteoglycans.

Unfortunately, researchers currently have few ways to systematically test how these sugars affect stem cell signaling. Ideally, scientists would like to make the cells display particular sugar chains to study their effects on differentiation. But engineering the sugars displayed on stem cells is not an easy task.

Surface Sugar
Credit: J. Am. Chem. Soc.
A portion of heparan sulfate (blue) is attached to a phospholipid tail (black) so the molecule can slip into membranes of mouse embryonic stem cells. The molecule contains a fluorescent dye (AF488) to help monitor its accumulation on cells.
Structure of proteoglycan mimic used to help stem cells differentiate.
Credit: J. Am. Chem. Soc.
A portion of heparan sulfate (blue) is attached to a phospholipid tail (black) so the molecule can slip into membranes of mouse embryonic stem cells. The molecule contains a fluorescent dye (AF488) to help monitor its accumulation on cells.

Kamil Godula of the University of California, San Diego, and his colleagues decided to create easily synthesized proteoglycan mimics that could insert into the membranes of stem cells.

The team wanted these mimics to carry heparan sulfate, which are chains of repeating disaccharide units speckled with different patterns of sulfate groups. It is difficult to synthesize these long chains and get specific sulfate patterns, so the researchers purchased 17 disaccharide units prepared by degrading the natural sugar chains. They attached each disaccharide to a polyacrylamide polymer containing a fluorescent tag. They then measured the relative affinity between FGF2 and each mimic through a fluorescence assay.

To test the mimic with the strongest affinity in mouse embryonic stem cells, the team added a phospholipid tail to the molecule so it would slip into the cells’ membranes. They added the lipid-labeled molecule to cells engineered to lack heparan sulfate. That meant that the proteoglycan mimic was the only sugar-containing structure to help FGF2 induce differentiation.

After six days, cells treated with the growth factor and the mimics changed into a neural rosette, a structure that forms when stem cells become precursors to nerve cells. The number of rosettes increased when cells were treated with more mimic. Untreated cells did not differentiate.

Godula says that one advantage of the method is its temporal control. The mimics disappear within hours when the cells naturally refresh their membranes. He hopes to design other molecules that stimulate particular differentiation pathways.

Stem cell researchers needed this new technology to allow them to engineer the sulfated sugars on cell surfaces, says Catherine L. R. Merry of the University of Manchester, in England. She wonders if the approach will work with growth factors that interact with longer sugar chains. A method to add sugars to the stem cell surface could reduce the cost of tissue engineering or stem cell therapy, Merry adds, because companies could induce differentiation using smaller amounts of expensive growth factors.


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