RT Journal Article SR Electronic T1 Tubule jamming in the developing kidney creates cyclical mechanical stresses instructive to in vitro nephron formation JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.06.03.494718 DO 10.1101/2022.06.03.494718 A1 John M. Viola A1 Jiageng Liu A1 Louis S. Prahl A1 Aria Huang A1 Trevor J. Chan A1 Gabriela Hayward-Lara A1 Catherine M. Porter A1 Chenjun Shi A1 Jitao Zhang A1 Alex J. Hughes YR 2022 UL http://biorxiv.org/content/early/2022/09/29/2022.06.03.494718.abstract AB The kidney develops through elaboration of ureteric bud tubules (the future urinary collecting ducts), stroma, and nephron progenitors in the cap mesenchyme that surround each tubule tip as they branch. Dynamic interactions between these tissues coordinate a balance between ureteric bud (UB) tip branching and nephron formation that sets nephron numbers for life, which impacts the likelihood of adult disease. How then is this balance achieved? Here we study the geometric and mechanical consequences of tubule tip crowding at the embryonic kidney surface and its effect on nephron formation. We find that kidney surface curvature reduces and tubule ‘tip domains’ 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. New tips overcome mechanical resistance as they branch, expand, and displace close-packed neighbors, after which residual mechanical stress dissipates. This correlates with a changing nephrogenesis rate over the tip ‘life-cycle’. To draw a causal link between the two, we mimic a mechanical transient in human iPSC-derived nephron progenitor organoids and find increased cell commitment to early nephron aggregates. The data suggest that temporal waves of mechanical stress within nephron progenitor populations could constitute a pace-maker that synchronizes nephron formation and UB tubule duplication after E15. Ongoing efforts to understand the spatial and temporal regulation of nephron induction will clarify variation in nephron endowment between kidneys and advance engineered kidney tissues for regenerative medicine.Competing Interest StatementThe authors have declared no competing interest.