Lab studies new method of cell communication

A research team led by Andre Levchenko of the Whiting School of Engineering has shed light on a previously poorly understood method of cell-cell communication called intercellular transfer of cellular components (ICT).

"Our findings are extremely surprising and somewhat controversial, changing the current dogmas of how cells can communicate with each other," Levchenko said. "We show that, under some circumstances, cells can also exchange such large components as membrane proteins or very large cytosolic molecules."

In multicellular organisms, otherwise unconnected cells can communicate by sending chemical signals to each other, like through the bloodstream, but they can also exchange molecules directly.

Although this phenomenon has been documented since 1995, scientists did not know how widespread ICT was among cells, nor the exact mechanism by which cellular components were shared.

This new study, which appears in the Journal of Cell Biology, provided evidence that ICT is widespread and that it occurs through temporary fusion of the cells involved.

Previous research in Levchenko's lab and one at Memorial Sloan-Kettering Cancer Center in New York had shown that a cancer-related protein could be transferred between tumor cells.

"We wondered if this phenomenon was restricted to just some proteins and cell types, or it could be widespread. Moreover, we also became interested in the mechanisms underlying the transfer process," Levchenko said.

ICT plays a role in many biological processes, including diseases. Past research on ICT has focused on glycosyl phosphatidylinositol (GPI)-anchored proteins in mouse and pig models. These are proteins that are very tenuously attached to the outside of the cell membrane and are easily exchanged between cells.

GPI-anchored proteins also bear prions, misfolded proteins that cause normal proteins to misfold on contact. This data suggests that prion diseases can be transferred through ICT. Probably the most infamous prion disease is mad cow disease, or its human variant, Creutzfeldt-Jakob disease. Tumor cells in vivo have also been found passing around proteins that confer resistance to multiple drugs.

By fluorescently labeling proteins and cell components and using flow cytometry, an experimental tool that allows scientists to sort and view single cells, researchers in Levchenko's lab concluded that cells were sharing these proteins when their membranes temporarily made contact and fused together.

"We found that this phenomenon is quite widespread, and moreover, that other parts of cells, including the membrane and cytosolic components could be transferred as well. The consequences of these findings are very interesting," Levchenko said.

Cells in multicellular organisms are constantly moving, whether randomly or actively. Their membranes are also dynamic - membrane proteins move laterally through the sheet of fluid phospholipids.

As cells near each other, the polar outer faces of their lipid membranes repel each other. The membranes may spontaneously fuse together to create a more stable state.

Then, proteins embedded or anchored in the membrane of either cell can be shared through lateral diffusion, the same mechanisms by which proteins rearrange themselves on a single cell's plasma membrane. More fluid membranes were found to lead to higher rates of transport.

"This phenomenon is quite general, as we have now demonstrated. We looked at multiple proteins and cell types. The mechanism we proposed based on the analysis had to account for this generality. Based on mathematical analysis and various predictions stemming from it validated in experiments, we proposed that the transfer is a consequence of transient cell-cell fusions occurring between motile cells, following cell-cell contacts (as cells 'bump' into each other during movement)," Levchenko explained.

Scientists in the study used Chinese hamster ovary cells to model the rate of protein transfer during ICT. They studied three proteins previously not implicated in ICT to test if the transfer was bi-directional. They discovered that either cell can transfer almost any membrane protein to the other.

For example, platelets travelling through the blood stream often fused temporarily with the endothelial cells lining the blood vessels. Labeled proteins on donor cells showed up on recipient cells and later migrated back to the original donor cells. Additionally, other parts of the membrane and small bits of cell cytosol are also exchanged in the process.

Fluorescently labeled particles located in the cytosol donor cells were moving into recipient cells for up to five days after initial contact. These particles are actually much larger than those that cells can exchange through gap junctions - more permanently opened doorways through which cells anchored together can exchange components.

Finally, researchers found that ICT between somatic and stem cells is much more efficient than ICT between somatic and somatic cells. Macromolecules as large as mRNA can be transferred between the two.

"The implications of this finding are very interesting, as one can imagine that if stem cells are used as a therapeutic tool, they might be able to acquire from neighboring cells not only the usual diffusible growth and differentiation factors, but also the receptors for them. This might make stem cells even more plastic in adopting the properties of the surrounding cells. If this can be manipulated, one can thus potentially affect stem cell therapy," Levchenko said.

The paper suggests that ICT is much more general than originally thought. The process can occur between any two types of cells and involve any proteins in the membrane or many components of the cytosol. The mechanism by which ICT occurs is the temporary fusion of two cell plasma membranes.

"This might allow cells to change their properties without tapping into their genomes, and for tissue properties to spread around constituent cells more easily. It still remains to be studied whether transient cell fusion is indeed the mechanism of this interesting phenomenon, as we hypothesize, and how the transfer can be inhibited or enhanced. But it is clear that we are dealing with a new and exciting chapter in our analysis of how cells can communicate with each other," Levchenko said.