A biohybrid system to reconstruct epithelial morphomechanics in vitro

Epithelial tissue compaction driven by smooth muscle contraction is central to epithelial morphogenesis and mechanotransduction. However, <i>in vitro</i> systems that recapitulate this mechanical process - especially those capable of mimicking the anisotropic and multi-axial nature of smooth muscle contraction - remain limited. Here, we present the biohybrid programmable epithelial tissue compaction system (BIOPRECS), consisting of an overlying contraction-responsive epithelial tissue (ET) and underlying thermo-responsive contractile hydrogel (CH). By coupling isotropic hydrogel contraction with defined epithelial geometric anisotropy, BIOPRECS enables programmable multi-axial epithelial compaction that mirrors <i>in vivo</i> processes. Its <i>in situ</i> culture-compatible setup allows straightforward examination of both tissue-scale folding and subcellular deformation, including cytoplasmic and nuclear responses. Furthermore, by modulating tissue geometry and boundary conditions, BIOPRECS reproduces organ-specific epithelial architectures reminiscent of those observed in the lung, intestine, and stomach. This system has a significant potential to become a powerful tool for investigating how mechanical compaction regulates epithelial morphogenesis and mechanotransduction.