Biomechanical regulation of cell shapes promotes branching morphogenesis of the ureteric bud epithelium

Abstract

Branching morphogenesis orchestrates organogenesis in many tissues including kidney, where ureteric bud branching determines kidney size and nephron number. We characterized 3D epithelial cell morphology, mechanisms regulating cell shape changes and their contribution to novel branch initiation in normal and branching incompetent bud tips. Machine learning-based segmentation of tip epithelia identified geometrical round-to-elliptical transformation as a key cellular mechanism facilitating growth direction changes in gaining optimal branching complexity. Cell shape and molecular analyses in branching incompetent epithelia demonstrated a failure to condense cell size and conformation, which with altered adhesive forces, defective actin dynamics, and MYH9-based microtubule organization suggest stiff cellular niche with disturbed sensing of and responses to biomechanical cues. The data collectively propose a model where epithelial cell crowding in tandem with stretching transform individual cells into elliptical and elongated shapes. This creates local curvatures that drive new branch formation during the ampulla-to-asymmetric ampulla transition of ureteric bud.