The movement of leukocytes across various substrates has been observed by scientists for a number of years. However, many of the precise molecular mechanisms have eluded investigators. Now, researchers at Aix-Marseille University have uncovered a new mechanism by which these amoeboid cells move, describing a new mechanism they call molecular paddling. The findings from the new study—published recently in Biophysical Journal through an article titled, “Amoeboid Swimming Is Propelled by Molecular Paddling in Lymphocytes”—could explain how both immune cells and cancer cells migrate in various fluid-filled niches in the body, for good or for harm.

“The capacity of living cells to move autonomously is fascinating and crucial for many biological functions, but mechanisms of cell migration remain partially understood,” explained co-senior study investigator Olivier Theodoly, PhD, head of the adhesion and inflammation lab at Aix-Marseille University in France. “Our findings shed new light on the migration mechanisms of amoeboid cells, which is a crucial topic in immunology and cancer research.”

Cells have evolved different strategies to migrate and explore their environment. For instance, sperm cells, microalgae, and bacteria can swim through shape deformations or by using a whip-like appendage called a flagellum. By contrast, mammalian somatic cells are known to migrate by attaching to surfaces and crawling. It is widely accepted that leukocytes cannot migrate on 2D surfaces without adhering to them.

This is a 3D videomicroscopy of the cytoskeleton of a swimming lymphocyte showing protrusions traveling along the cell body that mimics a breaststroke motion. [SoSPIM microscopy: L. Aoun, O. Theodoly, M. Biarnes, R. Galland]

Previous studies have reported that neutrophils could swim, but no mechanism was demonstrated. Another study showed that mouse leukocytes could be artificially provoked to swim. It is widely thought that cell swimming without a flagellum requires changes in cell shape, but the precise mechanisms underlying leukocyte migration have been debated.

In the current study, the research team provided experimental and computational evidence that human leukocytes can migrate on 2D surfaces without sticking to them and can swim using a mechanism that does not rely on changes in cell shape.

“Looking at cell motion gives the illusion that cells deform their body like a swimmer,” noted co-senior stud investigator Chaouqi Misbah, PhD, professor at Grenoble Alpes University. “Although leukocytes display highly dynamic shapes and seem to swim with a breaststroke mode, our quantitative analysis suggests that these movements are inefficient to propel cells.”

Instead, the cells paddle using transmembrane proteins, which span the cell membrane and protrude outside the cell. The researchers show that membrane treadmilling—the rearward movement of the cell surface—propels leukocyte migration in solid or liquid environments, with and without adhesion.

“We showed experimental and computational evidence that leukocytes do swim, and that efficient propulsion is not fueled by waves of cell deformation but by a rearward and inhomogeneous treadmilling of the cell external membrane,” the authors wrote. “Our model consists of a molecular paddling by transmembrane proteins linked to and advected by the actin cortex, whereas freely diffusing transmembrane proteins hinder swimming. Furthermore, continuous paddling is enabled by a combination of external treadmilling and selective recycling by internal vesicular transport of cortex-bound transmembrane proteins. This mechanism explains observations that swimming is five times slower than the retrograde flow of the cortex and also that lymphocytes are motile in nonadherent confined environments.

Interestingly, the cell membrane does not move like a homogenous treadmill. Some transmembrane proteins are linked to actin microfilaments, which form part of the cytoskeleton and contract to allow cells to move. The actin cytoskeleton is widely accepted as the molecular engine propelling cell crawling. The new findings demonstrate that actin-bound transmembrane proteins paddle and propel the cell forward, whereas freely diffusing transmembrane proteins hinder swimming.

The researchers propose that continuous paddling is enabled by a combination of actin-driven external treadmilling and inner recycling of actin-bound transmembrane proteins through vesicular transport. Specifically, the paddling proteins at the rear of the cell are enclosed inside a vesicle that pinches off from the cell membrane and is transported to the front of the cell. By contrast, the non-paddling transmembrane proteins are sorted out and do not undergo this process of internal recycling through vesicular transport.

“This recycling of the cell membrane is studied intensively by the community working on intracellular vesicular traffic, but its role in motility was hardly considered,” Theodoly concluded. “These functions of protein sorting and trafficking seemed highly sophisticated for swimming. Our investigations, to our surprise, bridge such distant domains as the physics of microswimmers and the biology of vesicular traffic.”

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