Tubule jamming in the developing kidney creates cyclical mechanical stresses instructive to in vitro nephron formation

Abstract The kidney develops through branching of progressively crowded ureteric bud (UB) tubules at the organ surface. The elongating tubule tips are surrounded by traveling cap mesenchyme niches consisting of nephron progenitors and separated by stromal boundaries. Dynamic interactions between these tissues coordinate a balance between UB tip branching, elongation, and nephron induction that sets nephron numbers for life, impacting the likelihood of adult disease. Such a crowded tissue environment could place geometric limits on the number of niches that can be formed while maintaining mechanical integrity of the tissue. Since space is at a premium, crowding could also force a given niche to prioritize between nephron formation or UB branching differently depending on its spatial context. Here we study the geometric and mechanical consequences of tubule tip crowding at the embryonic kidney surface. Organ curvature reduces and tubule ‘tip domain’ niches pack more closely over developmental time. These together create a semi-crystalline geometry of tips at the kidney surface and a rigidity transition to more solid-like tissue properties at later developmental stages. To infer mechanical dynamics over the branching timescale, we define a new method to infer tip domain ‘ages’ relative to their most recent branch events from fixed kidneys. We find that new tip domains overcome mechanical resistance as they branch and displace close-packed neighbors, transiently increasing mechanical stress in the niche. Ongoing efforts to understand geometric and mechanical effects on niche regulation will clarify variation in kidney tissue composition and advance engineering control strategies for synthetic regenerative tissues.