The Migratory Process

Migration is initiated as a cellular response to chemotac-tic gradients of soluble mitogens and haptotactic gradients of insoluble adhesive (ECM) molecules in the local microenvironment. Cell movement is mediated by the extension of thin, flat, membrane protrusions from the leading edge of the cell (Figure 1). These outward extending membrane processes are filled with a loose network of actin filaments and are known as lamellipodia; they are also sometimes referred to membrane ruffles when they are oriented perpendicular to the plane of the adhesive substrate. In some cells, formation of these membrane processes is accompanied or preceded by extension of long, thin protrusions filled with rigidified (cross-linked) bundles of actin filaments, known as filopodia, that act like moving cantilevers or fingers that explore the surrounding substrate. In fact, cells may extend and retract multiple filopodia and lamel-lipodia as they explore their microenvironment, suggesting that this process is a key regulatory event in directional migration and pathfinding.

First identified as the primary organelles of cell motility by Abercrombie in 1971, lamellipodia are sites of active actin polymerization, and their formation requires the local recruitment of a whole array of molecular components to mediate cytoskeletal reorganization. These include actin filament nucleating factors such as Arp 2/3 and SCAR; filament depolymerizing proteins such as cofilin; barbed-end capping proteins; and actin monomer binding factors such as profilin. Filopodia also form as a result of actin polymerization; however, these filaments are cross-linked into long, stiff bundles that can extend to up to tens of micrometers in length.

Other key structural elements in migrating cells are the adhesive contacts where the cells tightly attach to the underlying ECM. In migrating cells, the formation of these local

Figure 1 Diagram of a Migratory Cell. As the attachment sites between the intracellular cytoskeleton and the extracellular matrix (ECM), focal adhesions (gray ovals) transmit cell tractional forces to the substrate. In migrating cells, the formation of these local adhesive structures behind the leading edge stabilizes the extension of actin-based protrusions, such as lamellipodia and filopodia. The thin, sheet-like lamellipodium is characterized by a tight network of actin filaments and may be accompanied or preceded by the extension of filopodia containing rigid, cross-linked actin bundles. Forward motion requires direction extension of these processes from the leading edge, as well as exertion of cell tractional forces on the ECM substrate that help both propel the cell forward and release the cell's trailing adhesions.

Figure 1 Diagram of a Migratory Cell. As the attachment sites between the intracellular cytoskeleton and the extracellular matrix (ECM), focal adhesions (gray ovals) transmit cell tractional forces to the substrate. In migrating cells, the formation of these local adhesive structures behind the leading edge stabilizes the extension of actin-based protrusions, such as lamellipodia and filopodia. The thin, sheet-like lamellipodium is characterized by a tight network of actin filaments and may be accompanied or preceded by the extension of filopodia containing rigid, cross-linked actin bundles. Forward motion requires direction extension of these processes from the leading edge, as well as exertion of cell tractional forces on the ECM substrate that help both propel the cell forward and release the cell's trailing adhesions.

adhesive contacts, known as focal adhesions, at the leading edge of the cell helps stabilize the actin-based membrane protrusions. ECM regions beneath these spot weld-like focal adhesions also act as traction sites that resist tensional forces that are generated via actomyosin interactions in the cytoskeleton. This buildup of isometric forces restructures and stiffens the actin cytoskeleton behind the leading edge of the cell, thereby providing a stable platform from which the actin filaments that form filopodia and lamellipodia can assemble.

Importantly, cells also must be able to exert tractional forces and pull against their fixed ECM adhesions in order to propel the cell body forward and produce purposeful locomotion. During this process, the cell must generate enough motive force to overcome the resistance of the stiffness of its own cytoskeleton and of the ECM adhesions at its trailing edge (Figure 1). The extension of lamellipodia and the formation of new adhesions at the leading edge must also be spatially and temporally coordinated with detachment of adhesions in the trailing edge and release of the tail to result in net forward movement of the entire cell.

How To Reduce Acne Scarring

How To Reduce Acne Scarring

Acne is a name that is famous in its own right, but for all of the wrong reasons. Most teenagers know, and dread, the very word, as it so prevalently wrecks havoc on their faces throughout their adolescent years.

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