Mechanoresponse of Curved Epithelial Monolayers Lining Bowl‐Shaped 3D Microwells

Abstract The optimal functioning of many organs relies on the curved architecture of their epithelial tissues. However, the mechanoresponse of epithelia to changes in curvature remains misunderstood. Here, bowl‐shaped microwells in hydrogels are designed via photopolymerization to faithfully replicate the shape and dimensions of lobular structures. Leveraging these hydrogel‐based microwells, curved epithelial monolayers are engineered, and how in‐plane and Gaussian curvatures at the microwell entrance influence epithelial behavior is investigated. Cells and nuclei around the microwell edge display a more pronounced centripetal orientation as the in‐plane curvature decreases, and enhanced cell straightness and speed. Moreover, cells reorganize their actin cytoskeleton by forming a supracellular actin cable at the microwell edge, with its size becoming more pronounced as the in‐plane curvature decreases. The Gaussian curvature at the microwell entrance enhances the maturation of the supracellular actin cable architecture and leads to a vertical orientation of nuclei toward the bottom of the microwell. Increasing Gaussian curvature results in flattened and elongated nuclear morphologies characterized by highly compacted chromatin states. This approach provides better understanding of the mechanoresponse of curved epithelial monolayers curvatures lining lobular structures. In addition, bowl‐shaped microwells offer a powerful platform to study curvature‐dependent mechanotransduction pathways in anatomically relevant 3D structures.