Collagen-based three-dimensional (3D) in vitro models that recapitulate the structural and functional context of normal and malignant tissues provide a relevant surrogate to animal models in the study of developmental and carcinogenic processes. Human breast epithelial MCF10A cells embedded in a collagen gel formed both acinar and tubular structures only when the gel was detached (floating) from the cell culture plate's well, and allowed to be contracted by the cells. Epithelial phenotype depended upon the time and the location within the gel, as ducts formed exclusively on the upper layer of the gel while ductal branching occurred earlier in the central area of the gel, and gradually progressed toward the periphery. The addition of fibroblasts accelerated tubulogenesis. MCF10A cells facilitated the organization of thick collagen fibers packed into large bundles at the tip of the ducts and parallel to the direction of ductal elongation. In gels that were not detached from the well's wall, MCF10A cells organized in monolayer and collagen fibers were aligned along the axis of outstretched sprouts stemming from those cellular aggregates. Partial gel release induced uniaxial tubulogenesis associated with orderly aligned collagen fibers. These results suggest that proper collagen organization is necessary for epithelial morphogenesis to occur, and that biomechanical interactions between fibers and cells mediated duct formation, elongation and branching.
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