TISSUE IMAGING IN CELL BIOLOGY

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We have begun to study aspects of cell behavior in thick tissues: cell locomotion, cell proliferation and cell fusion. These fundamental biological processes in multicellular organisms have for many years been studied on cells isolated from tissue. However, in vivo, all these events are influenced by the complex, heterogeneous microenvironment of living tissue. We have developed a new approach to studying cell behavior which includes long-term culturing of blocks of unperturbed mouse and human tissues and confocal laser microscopy of individual cells inside these tissues. These newly developed techniques have been used to study tumor invasion of normal tissue. We have shown that the behavior of tumor cells is significantly affected by their surrounding normal tissue. An inhomogeneous tissue microenvironment results in nonuniform invasion of tumor cells which produce "streams" of cells following each other. This system provides an opportunity for direct observation of tumor invasion and raises the possibility of studying the effects of various drugs on this process. Thick tissue imaging was also implemented in vivo to test the mechanism of septic shock. Resistance arterioles of the rat cremaster muscle were imaged and the response to catecholamines was measured. Septic animals showed impaired vasoconstriction compared to controls. Inhibiting nitric oxide synthase reversed this hyporesponsiveness. By imaging the vessels actually responsible for the decrease of TPR seen in sepsis, pathophysiologic hypotheses can thus be directly tested rather than extrapolated from model tissues such as aorta.