Cell migration

Cell migration is a fundamental biological process essential for the development and maintenance of multicellular organisms. This movement allows for tissue formation during embryonic development, facilitates wound healing, and enables critical immune responses. Cells often navigate toward specific locations by responding to external stimuli, such as chemical signals or mechanical forces. When these movements are not properly orchestrated, the consequences can be severe. Such errors are linked to intellectual disability, vascular disease, tumor formation, and metastasis. Understanding these mechanisms is vital for creating new medical treatments to control invasive tumor cells.

Because cells exist in highly viscous environments, they experience a low Reynolds number. This means they must continuously produce force to maintain any movement. While simple organisms or sperm cells use flagella or cilia to swim, eukaryotic cell migration is much more complex. It typically involves drastic changes in cell shape driven by the cytoskeleton, which is the internal structural network of the cell. Scientists generally categorize these movements into two main scenarios: crawling motion and blebbing motility. Crawling is the most common method studied, often using fish epidermal keratocytes as a model.

Researchers study cell migration by using microscopy to observe cells attached to surfaces or in 3D environments. Because cell movement is quite slow, often only a few micrometers per minute, scientists use time-lapse microscopy to speed up the visible action. These videos show that the leading edge of the cell is highly active. This front area undergoes successive contractions and expansions to pull the cell forward. Common features of this movement include cytoplasmic displacement at the leading edge and the laminar removal of debris toward the trailing edge.

The cytoskeletal model is one primary theory explaining how the front edge advances. In this model, rapid actin polymerization occurs at the cell's front edge. Actin polymerization is the process where actin proteins build long filaments that physically push the leading edge forward. This serves as the main motile force for advancing the cell. Meanwhile, microtubules play a different role at the trailing edge, or the back of the cell. These microtubules act as struts that counteract contractile forces. When microtubules are dynamic, they can remodel to allow the tail to retract. However, if their dynamics are suppressed, they resist retraction and the cell struggles to move forward.

A second theory is the membrane flow model, which focuses on the cell's outer surface. This model suggests that the leading edge extends because internal membrane pools are returned to the cell surface there. This addition of membrane allows for the formation of a structured extension called a lamella. To keep crawling, the cell must also recycle its "feet," which are proteins called integrins. These integrins attach the cell to the surface it is crawling on. The cell undergoes endocytosis to bring these proteins to the rear, then uses exocytosis to move them back to the front for reuse.

Some cells perform adhesion-independent migration, meaning they do not need to stick to a surface to move. This type of movement is seen in neutrophils, macrophages, and certain metastatic cancer cells. In 1977, physicist E. M. Purcell theorized that objects could swim forward in low Reynolds number fluids through rearward surface flow. Experimental support arrived in 2010 when researchers discovered that amoeboid cells and neutrophils could move toward chemical attractants while suspended in a medium. Using optogenetics, scientists showed that these cells exhibit plasma membrane flow toward the rear. This flow exerts tangential forces on the surrounding fluid to propel the cell forward.

For successful movement, a cell must maintain polarity, meaning it has a distinct front and back. Without this polarity, a cell would simply spread in all directions. While the exact molecular origin of polarity is still being studied, it is linked to chemical gradients. At the molecular level, specific molecules like the phospholipid PIP3 and proteins such as Ras, Rac, and CDC42 are concentrated at the front. Conversely, molecules like PTEN and Rho GTPase are found toward the rear. This organization helps the cell maintain a stable direction, especially when moving toward a chemical signal.