Researchers at University of Toronto and Johns Hopkins University have identified a specific cellular structure that allows cells to sense fluid thickness. In their recent Nature Physics article, the group explains how cells respond to thickened fluids and details the effect of viscosity on cell movement.
Cells in the human body are constantly moving. Cell movement not only allows the body to form organs and deploy immune cells to sites of infection, but also contributes to the progression of diseases such as fibrosis and cancer metastasis. Fast movement of cancer cells is particularly detrimental to cancer patients as malignant cells can quickly leave the original lesion and form new tumors in other parts of the body.
This new study reveals the mechanism that allows cancer cells to travel significantly faster in cancerous tissue. The fluid surrounding cancer cells, just like the mucus that surrounds lung epithelial cells in cystic fibrosis patients, is extremely viscous.
Cell and Systems Biology Professor Sergey Plotnikov, who leads the Toronto team, was amazed how fast cells moved when they entered thick, mucus-like liquids. “Normally, we’re looking at slow, subtle changes under the microscope, but now we could see cells moving twice as fast in real time.”
Researchers determined that the cell’s ruffling edges are key sensors of fluid viscosity. In normal liquids, ruffles at the cell edge continuously move up and down like flapping cuttlefish fins; however, when viscous fluid is added, the ruffles quickly flatten, spread out and latch on to the surface beneath them.
But how do the ruffles help speed cells up when cells should be slowing down due to resistance from the viscous fluid? To understand the driving force behind this counterintuitive observation, the group developed mathematical models and performed an in-depth analysis of cell mechanics. The combined efforts showed that it is in fact the resistance forces that flatten the ruffles and initiate a sequence of events that promote cell spreading and fast movement.
Specifically, flattening of the ruffles increases the contact time between the cell edge and the surrounding surfaces, which enables the cell to assemble more attachment sites to its surroundings. Long columns of actin, rod-like structures that give a cell its shape, grow from the attachment sites and push the edges of the cell outward. This increase in spreading is accompanied by an increase in cell-exerted forces that collectively push the cell forward.
The mechanism that helps cells measure the viscosity of surrounding fluids is not limited to cancer cells. Fibroblasts and macrophages also display similar ruffles and move faster in thick liquids.
“The fundamental science of the paper is of great interest,” says Prof Christopher McCulloch at the Faculty of Dentistry at University of Toronto, who further comments that the effect of viscosity on cells involved in blood and lymphatic diseases could be exciting to study.
The full details can be found in the article titled “Membrane ruffling is a mechanosensor of extracellular fluid viscosity” at Nature Physics.