Morphogenetic process of a composite structure driven by contractile cells

In epithelial morphogenesis, fibroblast cells play a central role in shaping a tissue into a mature form. Nevertheless, fibroblast has been neglected in most of the previous studies designed to investigate the morphogenesis. They have focused on the epithelium itself without consideration of interactions between fibroblast and epithelial tissue. We developed a tissue-equivalent system in vitro containing fibroblast cells within the collagen gel stacked with a collagen vitrigel membrane (CVM) and an epithelium in series. As a result, we observed that fibroblast cells fold an epithelial layer, which guides cell migration and is accompanied by fibrous alignment across cells. Concurrently, we developed an agent-based model to mimic the experimental system. In the model, a collagen matrix and the CVM were individually simplified into a fibrous matrix and a stiff layer adhesively coupled to each other. fibroblast cells were coarse-grained into spherical contractile entities capable of migrating, located within the fibrous matrix and right beneath the stiff layer. Cells pull surrounding fibers, leading to cell migration, matrix remodeling characterized by fiber alignment, and CVM folding. These reciprocal events are consistent with experimental results. Our research broadens knowledge about the role of fibroblast in tissue morphogenesis.