New Mechanism of Cell Movement Revealed

In cells moving through a 3D matrix (top) the nucleus forms a tight-fitting piston with the cell membrane (dashed lines) to generate lobopodial movement. Cells moving on a 2-D surface with lamellipodia have space around the nucleus (arrowheads).Images by the researchers, courtesy of Science

Cells in the human body often need to move in particular directions. Cell movement is crucial for embryo development, immune defense, and tissue repair and regeneration. It’s also key in cancer progression, as metastatic cells spread throughout the body.

Researchers have closely studied how cells move on 2-D surfaces, such as tissue culture plates. Flat protrusions called lamellipodia form in the direction of movement. Movement is driven by actin—a major component of the cell’s skeleton, or cytoskeleton—and the molecular motor myosin.

A team led by Drs. Ryan J. Petrie and Kenneth M. Yamada at NIH’s National Institute of Dental and Craniofacial Research (NIDCR) recently observed a different type of movement while studying human fibroblasts, which play a critical role in wound healing. When moving within a 3-D matrix designed to mimic conditions in the body, the cells developed blunt, cylindrical protrusions termed lobopodia. Lobopodial movement, they found, also relies on actin and myosin. But its mechanisms were unclear.

In their new study, the researchers, along with Dr. Hyun Koo at the University of Pennsylvania, further examined fibroblasts moving in a 3-D matrix. Their study, funded by NIDCR, appeared in Science on August 29, 2014.

Lobopodial cells are marked along their sides by “blebs,” or bulges in the cell membrane. Membrane blebs can be caused by elevated pressure within the cell, so the researchers hypothesized that intracellular pressure might drive this type of motility. Using a micropressure sensor, they found that the pressure inside lobopodial cells moving in a 3-D matrix was substantially higher than that in cells moving with lamellipodia.

The scientists next examined pressure in different zones of the cell. Lobopodial cells, they found, had higher pressure in front of the nucleus and lower pressure behind it. In contrast, cells moving with lamellipodia had lower pressure both in front and behind the nucleus. Further experiments showed that the nucleus and other material divided lobopodial cells into 2 compartments.

Inhibiting contraction of actomyosin, a structure of actin and myosin, reduced pressure inside cells and caused a switch from lobopodial to lamellipodial movement. The team thus hypothesized that the tight-fitting nucleus might be pulled forward like a piston by actomyosin contractions to pressurize the front of the cell and form lobopodia. Indeed, live-cell microscopy revealed nuclei in lobopodial cells pulling forward and falling backward like a piston.

“When a cell is in the matrix, the nucleus tends to be at the back of the cell, and the cell body is very tubular in shape,” Petrie says. “It really looked like a piston.”

Other experiments identified the cytoskeletal filaments that transmit force to the nucleus. The protein nesprin-3 forms a crucial link for this pulling mechanism.

The team found a similar mechanism at work in other cell types as they moved through a 3-D matrix. Understanding how a cell’s environment can influence its movement will help researchers design better ways to control many biological functions.

—by Harrison Wein, Ph.D.