Control of Cell Motility by the Cytoskeleton and Extracellular Matrix

Amy Brock and Donald E. Ingber

Harvard Medical School and Children s Hospital, Boston, Massachusetts


Most past work in the area of angiogenesis and vascular development has focused on the importance of cell growth control. However, directional motility—the process by which endothelial cells migrate in a spatially oriented manner—is equally critical for tissue expansion and vascular pattern formation. For example, angiogenic factors can stimulate 2 millimeters of capillary outgrowth in normally avascular tissues (e.g., cornea) under conditions in which cell proliferation is inhibited; this occurs exclusively through endothelial cell elongation and directed movement. Repair of the endothelium after endarterectomy also involves migration of large vessel endothelium, and failure to reconstitute the continuous cell monolayer can lead to thrombus formation and vessel occlusion. Thus, it is critical that we unravel the mechanism by which local cues from the cell microenvironment drive cell migration in order to understand angiogenesis and other vascular disease processes. But how do cells interpret, integrate, and respond to information from their local environment and decide in which direction to move? This is a complex problem in light of the fact that their environment contains multiple soluble, insoluble, and mechanical stimuli that may provide conflicting signals to individual cells.

In this chapter, we review the current understanding of how cells sense these local signals and choose a direction in which to execute purposeful locomotion, with particular focus on the role of the cytoskeleton and mechanical interactions between cells and their extracellular matrix (ECM).

Insights into this mechanism have been made possible by recent development of new microtechnologies and tools that allow analysis of how microscale changes in physical parameters, such as ECM structure, topography, and mechanical compliance, impact directional cell motility and associated cytoskeletal signaling mechanisms.

Directional Motility

Directional cell migration on ECM is critical during all phases of embryonic development. For example, neural crest cells emigrate along a path defined by basement membrane fibrils during development of the nervous system. The ureteric bud epithelium migrates from the nephric duct toward the metanephric mesenchyme to induce the formation of the adult kidney. Formation of the vascular system follows a similar paradigm and is characterized by tandem cell migration during angiogenesis and migration of cell sheets during the expansion and repair of large vessels.

Angiogenesis relies on the tight control of endothelial cell migration through the balance of angiogenesis inducers and inhibitors. This dynamic, multistep process involves retraction of pericytes from the abluminal surface of the capillary, release of proteases that degrade the ECM surrounding the preexisting vessels, and endothelial cell migration in the direction of an angiogenic stimulus that is mediated by ongoing deposition (and degradation) of new ECM components. This is followed by cell proliferation, which facilitates further extension of the growing capillary

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sprouts. Eventually, these structures locally slow down their rate of ECM turnover, accumulate a basement membrane, and reorganize into quiescent, hollow, capillary tubes. Recruitment of pericytes and smooth muscle cells further stabilizes these newly formed blood vessels.

In the adult, cell migration during angiogenesis is critical for normal function of the female reproductive system as well as wound healing and the immune response. Directed cell movement is also a feature of the tissue remodeling that occurs during postnatal developmental processes, such as branching morphogenesis of the mammary epithelial ductal system and elongation of the ureters in the renal system. In the subventricular zone, an area of the brain containing neural stem cells, neurogenesis occurs throughout adulthood, with the majority of these new neurons migrating anteriorly into the olfactory bulb, traveling a distance of several millimeters in a highly directed manner to reach their destination. Thus, understanding of the mechanism by which directional cell movement is controlled has important implications for many developmental systems.

Cell motility also is a central component of various pathological conditions and as such may represent a common target for drug development. Tumor expansion requires the proliferation and directional migration of endothelial cells as blood vessels are recruited to supply a solid tumor with oxygen. If this angiogenic process is inhibited, the tumor must rely on preexisting blood vessels, and its growth will be checked at a maximum size of approximately 1 to 2 millimeters in diameter because of diffusion limitations. Metastatic tumor cells also acquire the ability to migrate out of the primary tumor into the vasculature and subsequently invade a secondary location. In the vascular system, misdirected endothelial cell migration is a key factor in vascular anomalies, intimal hyperplasia secondary to endarterec-tomy, and chronic inflammatory diseases such as arthritis and atherosclerosis.

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