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Platforms involving ECM protein or hydrogel encapsulation have been used to demonstrate that geometry of an embedded 3D tissue can drive tube morphogenesis and cancer invasion through endogenous stress patterns. Microwell based platforms have emerged as a method to create large numbers of replicate multicellular structures for use in drug screening, disease modeling, and stem cell culture. Since basic parameters, such as size, can affect cell and aggregate behavior, careful engineering is required to investigate cell response to a 3D environment. As 3D culture platforms have become more widely utilized, those that more specifically address mechanical loading and signaling have also been developed. Compared with those on 2D, cells in 3D experience distinct mechanical stresses which influence their biological functions in embryonic development and tumor growth. Three-dimensional culture is more representative of in vivo conditions owing to increased cell-cell interactions and freedom for motility and reorganization, which are especially important in differentiation and morphogenesis. Much of the work relating stem cell behavior to mechanical conditions, such as stiffness, geometry, and cell generated force, has been constrained to two-dimensional culture systems. Mechanical force and mechanical signaling have been established as key to stem cell development and tissue behavior. The differentiation and morphogenesis of progenitor cells into functioning tissues is orchestrated through a diverse set of biochemical cues from neighboring cells and other elements of microenvironment. It also can serve as a platform for the further investigation of tissue morphogenetic signaling mechanisms in the liver as well as other stem cell differentiation contexts. Overall, this combined approach that integrates microscale fabrication, imaging and analysis, and mechanical modeling serve as a demonstration of how microtissue geometry can drive patterning of mechanical stresses that regulate cell differentiation trajectories. We used finite element modeling to predict stress distributions in these microtissues which demonstrated that cell-cell tension correlated with hepatocytic fate, while compression correlated with decreased hepatocytic differentiation and increased biliary differentiation.
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Biliary differentiation was distributed throughout the microtissue interior regions and was additionally increased in toroid tissues compared to cylinder tissues. These studies demonstrated patterning of hepatocytic differentiation to the outer shell of the cylinder and toroid microtissues, except at the inner diameter surface of the toroid tissues.
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We fabricated 3D liver progenitor cell microtissues of varied geometries, including cylinder and toroid, and used image segmentation on confocal images to track individual single cell phenotype within defined spatial coordinates. We applied this platform to a model liver development system to investigate the impact of tissue geometry and mechanical stress on liver progenitor cell bipotential differentiation into hepatocyte-like and biliary-like cells. Towards this, we implemented a hydrogel microwell based method to produce arrays of multicellular microtissues in constrained geometries, which cause distinct profiles of mechanical signals in 3D. Investigating the role of mechanical signaling on stem and progenitor cell differentiation in three-dimensional (3D) microenvironments is key to fully understanding these processes.