Engineers ask how cells become unstuck

You might imagine that most of the cells in your body remain in one place for their entire lives, keeping you from resembling a giant mound of silly putty. However, controlled cell movement plays a key role in many necessary biological processes.

A research team lead by Bridget Wildt, Denis Wirtz and Peter Searson at the School of Engineering has become the first to measure and model the dynamics of programmed cell detachment from their substrates.

Cells are normally kept tethered in place through a framework of proteins called the extracellular matrix (ECM) that surrounds each cell.

Cellular detachment and migration is necessary in such diverse processes as the development of neural synapses during embryonic development, the immune response of neutrophils to infection and the metastasis of tumor cells.

To model the moment at which cells detach from the ECM in the laboratory, the scientists attached many copies of a short peptide (RGD, or arginine-glycine-aspartic acid) to a small gold-lined chip. When cells are exposed to the chip, proteins embedded in the plasma membrane called integrins bind to the RGD sequences the same way that integrins bind to the ECM in an organism.

A mild jolt of electricity to a gold electrode causes the RGD sequence to detach from the chip, bringing the cell along with it. The RGD chip provides a good model of in vivo cell dynamics.

"We have performed experiments showing that the exponential cell contraction dynamics are the same for spontaneous cell contraction or 'tail snap' observed during normal cell motility," Searson, professor of Materials Science and Engineering, said.

"The problem with studying normal tail snap is that there is no way to know when the cell initiates the contraction process. Our method overcomes this problem."

Using their model, the scientists found that after the electric shock but before the cells detach, there is a waiting time, or induction time. Then, the part of the cell contacting the chip contracts, and finally the whole cell detaches.

On average, the induction time was 57 seconds after the voltage was applied, and after that the cells took an average of 39 seconds to contract before detachment. Part of this time is used for the cell to overcome internal friction and friction with its substrate.

The scientists also used fluorescently labeled actin filaments, which the cell uses to contract, to model the contraction stage.

"Using live cell imaging, we have shown that the actin fibers at the attachment points actually release and contract before the cell membrane," Searson said.

Cell detachment is precisely timed and regulated in multicellular organisms, and the researchers hope to gain greater understanding of the molecular mechanisms behind cell detachment using molecular inhibitors for signal pathways and cell structure components.

Cell detachment is also an important part of many disease processes. The spread of many cancers depends on detachment.

"We are [also] studying the detachment of cancer cells to improve our understanding of cell detachment from tumors," Searson said.