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, in vitro 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 in vivo processes. Its in situ 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.