Just like birds migrate as changes in the environment influence their internal compass, cells in the human body have an inner compass that signals them to migrate in response to changes in tissues that make up the different organs. Shedding light on how cells use this internal compass to polarize, i.e. establish a front-rear axis, and migrate directionally is essential to understanding development and disease.
After three years of intense work, Sankar P. Chaki, a postdoctoral research associate in the Department of Veterinary Pathobiology at the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM), has identified a molecular mechanism that coordinates an “inner compass” that enables directional cell migration. Chaki, working in the laboratory of Gonzalo Rivera, was looking for links between changes in the morphology of vascular endothelial cells and their ability to set and maintain a particular direction while crawling on two-dimensional surfaces.
“Cell migration is currently an area of very active research,” Rivera said. “Recently, our group joined hundreds of scientists from around the globe that gathered at the Gordon Research Conference on Directed Cell Migration, held in Galveston, TX, to discuss topics ranging from basic molecular and cellular mechanisms and function, to new imaging technology, to new therapeutic interventions. Understanding regulation of cell migration is the key to developing new therapies to alleviate conditions that involve either activation or inhibition of cell migration.”
Rivera further explained that tissue repair and wound healing are examples of conditions that require stimulation of cell migration; whereas, the progression of invasive cancers, arthritis and certain cardiovascular-related disorders, could be restricted by inhibition of cell migration.
Cells orient themselves during the process of migration by two essential regulatory mechanisms. One of them is dictated by the presence of external signals ““ either attractants or repellents. The other operates as a cell’s inner compass, a built-in molecular mechanism that enables the establishment of cell polarity, i.e. the formation of distinct front and rear ends and directional migration.
“Cell polarization sets in motion a molecular process that enables directional cell migration by coordinating changes in cell shape, cell-cell contacts, and cell adhesion to the surface,” Chaki explained. “Using a combination of molecular genetics, cell biology and advanced imaging techniques, we showed that Nck adaptors are key components of the molecular machinery that coordinates intrinsic cell directionality. Nck adaptors modify the actin cytoskeleton ““ a meshwork of filaments that controls cell shape and motility ““ and contribute to directional migration by coordinating the formation of crawling pseudopods ““ or foot-like extensions ““ that adhere to the surface.”
Intrinsic cell directionality is observed when cells respond to a non-directional, uniform signal that triggers the basic motility machinery in the absence of any external guidance factor. Vascular endothelial cells with depletion of Nck adaptors exhibit loss of cell polarity ““ failure to establish a clear front and rear end ““ and impaired directional migration, i.e. inability to sustain directionality while crawling.
These findings from Rivera’s laboratory, accepted for publication in the highly regarded Journal of Cell Science, are significant because they establish new potential targets in diseases that involve altered cell migration and invasion such as cancer metastasis and atherosclerosis.
Rivera emphasized the multi-disciplinary nature of this research. “We succeeded in integrating a team that combines expertise in cell biology, biophysics, imaging technology and computer-assisted image analysis. The team of collaborators includes Andreea Trache (TAMU HSC), Rola Barhoumi (CVM Image Analysis Laboratory) and Shawn Gomez (University of North Carolina). We are also grateful for the support provided by the American Heart Association, Department of Veterinary Pathobiology and Texas A&M University,” Rivera said.
An ongoing research project in the laboratory is examining the role of Nck adaptors and cytoskeletal remodeling in the establishment of polarity and lumen formation in vascular networks developing in three-dimensional environments that more accurately resemble the organization of tissues in the body.
The full research article can be accessed at: http://jcs.biologists.org/content/early/2013/02/21/jcs.119610.long.
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