Using Peptides to Reset a Diseased Cell


Researchers at the University of California, San Diego School of Medicine have published a series of proof-of-concept experiments that demonstrate the ability to direct medically relevant cell behaviors by artificially manipulating a central hub in cell communication networks. The manipulation of this communication node, which was reported in the journal Proceedings of the National Academy of Sciences, makes it possible to reprogram major parts of a cell’s signaling network instead of targeting only a single receptor or cell signaling pathway.

This discovery could have tremendous clinical value, since it could slow or reverse the progression of diseases, such as cancer, which are driven by abnormal cell signaling along a variety of signaling pathways.

“Our study shows the feasibility of targeting a hub in the cell signaling network to reset aberrant cell signaling from multiple pathways and receptors,” said senior author Pradipta Ghosh, MD, an associate professor of medicine.

The UC San Diego team engineered two small protein fragments, known as peptides, to either turn on or turn off the activity of a family of proteins called G proteins. G protein-coupled receptors, which are embedded into the surfaces of cells, are used by cells to sense and respond to their environments. Approximately 30 percent of all prescription drugs target cells by binding to and affecting G protein-coupled receptors.

G protein coupled receptor cycle

Several laboratories, including those at UC San Diego, have discovered that G proteins can also be activated inside cells, and not simply on cell surfaces. Other receptors can activate the internal components of the G protein-coupled receptor, as can a protein called GIV. GIV has been implicated in cancer metastasis and other disease states. Both the “on” and “off” peptides were made from parts of the GIV protein receptor.

In a series of cell culture experiments, the “on” peptides were shown to accelerate the ability of the cells to migrate after scratch-wounding, which is a process linked to wound healing. The “off” peptide, in contrast, reduced the aggressiveness of cancer cells and decreased the production of collagen by cells associated with liver fibrosis. In experiments with mice, the topical application of the “on” peptides helped skin wounds heal faster.

“The takeaway is that we can begin to tap an emerging new paradigm of G protein signaling,” Ghosh said.

Taste Stem Cells Identified


Researchers at the Monell Center in Philadelphia, PA have successfully identified the location and markers for taste stem cells on the tongue. These findings will almost certainly allow scientists to grow and manipulate taste cells for clinical and research purposes.

Neurobiologist Robert Margolskee with the Monell Center who was also one of the authors of this study said: “Cancer patients who have taste loss following radiation to the head and neck and elderly individuals with diminished taste function are just two populations who could benefit from the ability to activate adult taste stem cells.”

Taste cells are located in rosette-like clusters known as taste buds in bumpy structures called papillae on the upper surface of the tongue. Two types of taste cells contain chemical receptors that initiate the perception of sweet, bitter, unami salty, and sour taste qualities. A third type of taste cell appears to serve as a support cell for these taste cells.

Gustatory_receptor_cell

A truly remarkable characteristic of these sensory cells is that they regularly regenerate, and all three taste cells undergo frequent turnover. The average lifespan of these cells is 10-16 days, which means that constant regeneration must occur in order for these cells to replace the cells that constantly die.

For decades, scientists who study taste have tried to identify the stem cell population that form these different taste cells. Scientists were also completely uncertain as to the location of these taste cell progenitors. Where they in the taste buds, near the taste buds, or someplace entirely different?

Monell scientists drew upon the strong association between oral taste cells and endocrine cells in the intestine. They reasoned that the cell-surface markers for stem cells in the intestine might also serve as markers for stem cells in the tongue. By using antibodies to a surface protein called Lgr5 (leucine-rich repeat-containing G-protein-coupled receptor 5), the Monrell team observed two strong expression patterns for this marker in the tongue. One signal was underneath taste papillae at the back of the tongue and the second signal was an even weaker signal underneath taste buds in those papillae.

The Monell group hypothesized that the two levels of expression could indicate two different populations of cells that expressed Lgr5 at different levels. The stronger-expressing cells are probably the actual stem cells and those that more weakly express Lgr5 are those progeny of these stem cells that are beginning to differentiate. Therefore, the expression of the stem cell marker in these cells is fading.

Additional work showed that Lgr5-expressing cells were capable of differentiating into any of the three different types of taste cells.

Peihua Jiang. who is also a neurobiologist at the Monell Center, said: “THis is just the tip of the iceberg. Identification of these cells opens up a whole new area for studying taste cell renewal, and contributes to stem cell biology in general.”

In the future, the Monell group plans to program the Lgr5-expressing cells to differentiate into the different taste cell types, and explore how to grow these cells in culture. This will create a renewable source of taste receptor cells for research and perhaps even clinical use.

See Karen Yee, et al., “Lgr5-EGFP Marks Taste Bud Stem/Progenitor Cells in Posterior Tongue.” Stem Cells 2013 DOI: 10.1002/stem.1338.