Modeling tissue-specific signaling and organ function in three dimensions

Abstract

IntroductionQualitative evaluation of the cellular complexity and structural integrity of organ biopsies has been used by pathologists for decades to gain insight into human diseases. The well-accepted correlation between tissue structure and health or disease conveys important lessons for the development of experimental models for the study of normal human biology and associated disease progression. Optimally, model design should recapitulate both the 3D organization and the differentiated function of any given organ but at the same time allow experimental intervention. By doing so, cell-based models facilitate systematic analyses that address, at the molecular level, how normal organ structure and function are maintained or how the balance is lost in cancer.Because of the ethical, technical and financial constraints inherent in research on human cells and tissues, the demand for models that faithfully parallel human form and function considerably outweighs the supply. We and others asserted more than two decades ago that development of physiologically relevant models of both rodent and human origin should recognize that organs and tissues function in a 3D environment (Elsdale and Bard, 1972;Hay and Dodson, 1973;Bissell, 1981;Ingber and Folkman, 1989). Further, that in the final analysis, the organ itself is the unit of function (Bissell and Hall, 1987). We now know that exposure of cells to the spatial constraints imposed by a 3D milieu determines how cells perceive and interpret biochemical cues from the surrounding microenvironment [e.g. the extracellular matrix, growth factors and neighboring cells (for reviews, see Roskelley et al., 1995;Bissell et al., 2002;Cunha et al., 2002;Ingber, 2002;Radisky et al., 2002)]. Furthermore, it is in this biophysical and biochemical context that cells display bona fide tissue and organ specificity.Here, we describe studies of epithelial-cell-based systems that demonstrate the importance of developing and utilizing 3D human organotypic models to understand the molecular and cellular signaling events underlying human organ biology (Fig. 1). In their most simplistic form, these models comprise homogeneous epithelial cell populations that are cultured within 3D basement-membrane-like matrices. These relatively simple 'monotypic' cell models have progressively evolved into 3D co-culture models containing multiple cell types, which approximate organ structure and function in vitro and enable systematic analyses of the molecular contributions of multiple cell types. Finally, we go on to explore how human 3D culture models are being coupled to existing technologies in the mouse to generate models in vivo that could elucidate the fundamental influence of stromal-epithelial interactions in normal organ function as well as those that perturb organ homeostasis and lead to disease. As a result of these advancements, we are equipped with a hierarchy of related models that appreciate the importance of 3D environments but vary with respect to cellular complexity. By using this collectio...

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