Surface Stresses Drive Morphological Changes in Three-Dimensional Microtissues*

The formation and maintenance of tissue boundaries is vital for morphogenesis and homeostasis as groups of cells with distinct functions must often be kept physically separated. Cells organize into sheets on the tissue surfaces by forming intercellular mechanical connections directly or through the ECM. The collective dynamics of boundary regulation have been extensively studied with micropatterned epithelial monolayers, whose behavior has been captured using physical models based on nematic liquid crystals. However, less is known about surface effects in 3D fibrous tissues and their contribution to tissue architecture. We developed a high-throughput biomimetic platform for the study of morphogenesis in multilayered 3D microtissues. We performed local mechanical perturbations using a robotic microsurgery system and selective optochemical manipulations using a programmable projector. We show both experimentally and by using computer simulations that cells at the tissue boundary develop surface stresses and, together with contractile cells residing in the core, drive macroscale deformation. We demonstrate that targeted elimination of cells at the tissue surface induces a local stress gradient that leads to tissue morphogenesis.