Like the coordinated movements of bird flocks and fish schools, cells possess the ability to migrate within the body. Understanding the mechanisms underlying their choreographed movements unveils the secrets of many vital processes from embryo development to wound healing and cancer metastasis.
Download this Explainer Article from Drug Discovery News to learn why cells migrate, how they navigate diverse environments and move together in groups, and how researchers can leverage this knowledge for therapeutic advancements.
Cells possess a remarkable ability to move. Understanding the mechanisms underlying their choreographed movements unveils the secrets of many biological processes.
BY YUNING WANG, PHD · ILLUSTRATED BY EMILY LAVINSKAS
When microbiologist Antonie van Leeuwenhoek first peered at bacterial cells through his microscope, he described these motile entities as little animalcules. Today, scientists know that cell movement is a fundamental process in all living organisms. Cells frequently move through crowded microenvironments and travel long distances to reach remote tissues, enabling diverse biological phenomena in health and disease.
Why do cells migrate?
Cell migration begins from the earliest stage of an animal’s life. As the embryo develops, it transforms from a continuous epithelial sheet of cells into a complex, multidimensional structure that gives rise to diverse tissue shapes. The pivotal force of this transformation is the migration of embryonic epithelial cells, which move inward to form three primary germ layers. Cells in these layers continue to move, reaching their designated locations within the embryo, where they specialize into distinct cell populations (1). These early migration events determine the precise shape and position of cells during organogenesis, crafting the ultimate architectures of tissues and organs in the adult body.
In adult organisms, cell migration remains prominent. During wound healing and tissue regeneration, fibroblasts migrate from underlying tissue layers to replace old or damaged cells, maintaining tissue integrity and homeostasis. Immune cells constantly patrol the body, exiting the bloodstream and entering the tissue during immune responses (2). Such motility allows them to effectively defend the body against pathogens and foreign invaders.
To ensure proper functioning, the body precisely regulates cell migration in space and time. When cells fail to migrate correctly, severe pathological conditions can occur, including birth defects, chronic wounds, and immune deficiencies. Similarly, undesirable migratory events can lead to detrimental consequences like metastatic cancer, where tumor cells break free from their origins to invade normal tissues (2).
What determines the direction of cell movement?
More than a century ago, microbiologist Theodor Wilhelm Engelmann from the University of Utrecht and botanist Wilhelm Pfeffer from the University of Tübingen discovered that bacteria migrated toward nutrient sources and away from noxious acids (3). Since then, scientists have found that cells within multicellular organisms also react to diverse chemical stimuli in their environments, including small peptides, metabolites, growth factors, and chemokines. When these agents form a gradient, cells orient their movement along the gradient in a phenomenon known as chemotaxis (4). Such gradients are transient, typically directing cells to migrate toward or away from the gradient sources over short ranges. Interestingly, migrating cells can generate the gradients themselves. They achieve this by secreting enzymes that degrade the initially distributed chemotactic agents in the environment, giving rise to a steep local gradient. As a result, the gradient constantly moves with the cells, allowing them to traverse long distances (4).
The extracellular matrix (ECM) contains a multitude of fibrous proteins such as fibronectin, laminin, collagen, and elastin that provide adhesion sites for cells. Variations in concentrations of these ECM proteins generate adhesion gradients. Similar to chemotaxis, cells migrate along these gradients in a process called haptotaxis (4). ECM proteins bind to chemotactic agents secreted by cells, creating immobilized gradients that serve as migration cues. During haptotaxis, migrating cells may deposit or break down ECM proteins. This remodels the ECM and modifies the haptotactic gradient, enabling cells to navigate toward specific locations.
In addition to chemical cues, mechanical and electrical stimuli also dictate the direction of cell movement. In a behavior known as durotaxis, cells sense extracellular rigidity and tend to migrate toward stiffer parts of the ECM. ECM stiffness arises from the crosslinking of ECM components such as collagen and fibronectin. While moving, migrating and surrounding cells can actively modulate ECM stiffness by depositing or degrading ECM components (5). Galvanotaxis, on the other hand, is directed cell motion guided by electric fields. For example, when an injury occurs, ions seep from damaged cells, producing abnormal electrical currents. The detection of these electric fields by nearby cells triggers their migration toward the wound to facilitate healing (5).
How do cells move?
When moving on a 2D substrate, cells go through repetitive cycles of protrusion, adhesion, and contraction (6). In this cycle, the cell first protrudes lamellipodia, sheet-like projections composed of branched actin filaments, at its leading edge. Next, the cell establishes temporary adhesions to the substrate via integrins that bind to the matrix. These adhesions connect to the contractile actomyosin fibers within the cell, which pull from the front and squeeze from the rear, driving the cell body forward. After the cell body advances, the rear detaches from the substrate. The cycle then repeats with new cell protrusions at the leading edge.
In contrast to in vitro 2D substrates, cell movement in 3D living tissues faces more challenges as cells must navigate through a complex network of ECM barriers and surrounding cells. To accomplish this, cells employ different migratory modes, including mesenchymal, amoeboid, and lobopodial.
Mesenchymal cells, which are multilineage cells capable of self-renewal and differentiation into various cell types, orient themselves along the ECM fibers, while secreting proteases that digest a tunnel in the ECM. The microtubule-organizing center within mesenchymal cells is located ahead of the nucleus, facilitating the delivery of protease-loaded vesicles to the cell front for ECM remodeling (7).
In amoeboid migration, cells exhibit a rounded morphology and undergo extensive shape changes, resembling a moving amoeba. This migration mode requires few adhesions to the ECM. Instead, the cell forms actin protrusions or spherical membrane bulges called blebs and moves by extending these blebs through narrow pores in the ECM. The nucleus, which is typically located in the cell front, serves as a ruler that gauges the diameter of pores within the ECM, guiding the cell to choose the path with minimal resistance (7).
Often found in a highly crosslinked ECM, lobopodial migration exhibits features of both amoeboid and mesenchymal migration. The cell creates bleb-like protrusions called lobopodian at its leading edge. At the same time, the cell firmly attaches itself to the substrate, and the contractile actomyosin fibers pull the nucleus forward like a piston in a cylinder to generate pressure at the front, propelling the cell ahead (7).
Various factors including cell-ECM adhesions, protrusion types, cellular contractility, and proteolytic capacity influence cell migration. Cells adapt or switch between different migratory modes, opting for the most suitable approach to advance themselves.
How do groups of cells move together?
Some cells travel and find their ways individually. However, during the development of multicellular organisms, tissue regeneration, and tumor dissemination, cells often team up to form sheets, sprouts, strands, tubes, or clusters for more efficient migration. This collective movement typically begins with a process known as epithelial-to-mesenchymal transition (EMT), where static epithelial cells acquire migratory properties to transform into mesenchymal cells (7).
Once these motile mesenchymal cells form, they come together and join forces. Adjacent cells establish interactions between their surface receptors, which connect to the actin cytoskeletons within cells. This interconnectedness enables the cells to communicate and transmit forces among each other. Cells that lose contact with their adjacent partners halt their migration until they reconnect to the collective (7). By utilizing different adhesion receptors and cytoskeletal systems, cell-cell adhesions can be transient or stable, tight or loose, enabling diverse forms of collective cell migration (8).
During collective migration, leader cells pioneer the way. They sense the surrounding microenvironment and guide the direction and speed of follower cells. When exposed to environmental cues such as ECM fibers, chemokines, or growth factors, leader cells polarize themselves along the migration direction, elongate their shapes, and extend protrusions. To drag follower cells behind, leader cells transmit forces through their interconnected cytoskeletons as well as release chemotactic signals that prompt the follower cells to move. Additionally, while moving through the 3D environment, leader cells actively modify their migration paths by interacting with the ECM and secreting proteases that break down ECM fibers, facilitating follower cells’ movements (8).
While leader cells guide the migration paths, follower cells help maintain the unity of the team. When two migrating cells come into contact, they undergo contact inhibition of locomotion (CIL). During CIL, both cells stop moving toward each other, retract their protrusions, and diverge in separate directions. This prevents follower cells from producing protrusions or stacking up on one another. As a result, only leader cells at the front edge maintain their protrusions in the direction of migration, ensuring a uniform cell polarity across the entire cell cluster (9).
How do migratory cells stop moving and settle into their new environments?
Following an arduous journey, migrating cells settle at their intended destinations to execute their functions. Circulating immune cells stop moving once they encounter chemokines immobilized within the vascular lumen produced by endothelial or other immune cells near an infection. Binding these chemokines activates integrins on immune cells’ surfaces, leading to their adherence to endothelial cells, which prompts them to exit the circulatory system and move toward an infection site (10). Metastatic cancer cells in blood vessels use a similar mechanism to leave the bloodstream and invade surrounding tissues (11).
To adapt to their new surroundings, migratory cells establish stable connections with local environments. In the case of embryonic development, once migratory mesenchymal stem cells (MSCs) reach their target regions, they express specific cell adhesion molecules such as cadherin, which tightly stick the cells together, forming a condensed cluster (12). As cell-cell interactions increase, the cells rearrange their actin cytoskeletons, changing their shapes from spread to round. During this condensation, MSCs also deposit new ECM components such as fibronectin, introducing additional contact sites to stabilize the already arrived cells and accommodate incoming ones (13). The high cell density and fibronectin-rich matrix make a conducive environment for MSCs to shift into the differentiation phase, leading to the development of a range of tissues such as cartilage, bone, fat, skeletal muscle, and neurons. Likewise, during wound healing, fibroblasts that have migrated to the wound secrete various ECM components, including collagen and fibronectin, which create a provisional scaffold that fosters epithelial cell proliferation and drives tissue regeneration (14).
Tracking every cell step
Much like zoologists utilize radio telemetry and geolocation devices for tracking animal movement in the wild, scientists employ specialized tracking tools to study cell migration. Various microscopy techniques enable real-time visualization of cell movement within living organisms through fluorescent labeling or genetic modification. These methods are typically applied to laboratory animals like mice and zebrafish.
Human cell migration studies rely on in vitro methods, such as transwell chambers, which consist of a permeable membrane that separates two compartments in a culture dish. Cells in the upper chamber migrate toward a chemotactic agent in the lower chamber (15). By quantifying the number of cells that successfully cross over, scientists can gain insights into the cells’ migratory abilities in response to different stimuli. Recent advances in microfluidics and organ-on-a-chip technologies have revolutionized human cell migration research. These innovations recreate cellular microenvironments, facilitating the precise manipulation of factors that affect cell migration. For example, 3D microfluidic devices with biochemical and biophysical cues mimic pathophysiological conditions associated with different tumor progression events, enabling scientists to closely follow each stage of cancer metastasis (16). These devices may also help uncover crucial factors in immune and neurological disorders and discover novel drugs that target specific steps of aberrant cell migration.
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