The developing murine kidney actively negotiates geometric packing conflicts to avoid defects

Prahl, L.; Viola, John M.; Liu, Jiageng; Hughes, Alex J.

doi:10.1016/j.devcel.2022.12.008

Cited by 5 publications

(19 citation statements)

References 68 publications

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“…This perspective is satisfying when averaged over niches, but does not explain how e.g. differentiation cues are regulated in response to radical changes in niche geometry caused by growth and splitting cycles synchronized with UB branching events 4,16 . Therefore, an emerging area of interest is to determine potential geometric and mechanical factors that may add context-dependent cues to cell decision-making in and adjacent to nephron progenitor niches.…”

Section: Discussionmentioning

confidence: 95%

“…Kidney immunofluorescence imaging. Immunofluorescence staining and imaging was performed as previously described 16 , using protocols adapted from Combes et al and O'Brien et al 104,105 . Briefly, dissected kidneys were fixed in ice cold 4% paraformaldehyde in DPBS for 20 min, washed three times for 5 min per wash in ice cold DPBS, blocked for 2 hr at room temperature in PBSTX (DPBS + 0.1% Triton X-100) containing 5% donkey serum (D9663, Sigma), incubated in primary and then secondary antibodies in blocking buffer for at least 48 hr at 4 o C, alternating with 3 washes in PBSTX totaling 12-24 hours.…”

Section: Methodsmentioning

confidence: 99%

“…Quantitative principles of this software environment are detailed in ref. 16 . We used the SphereCollide goal to model sphere mutual repulsion and the OnMesh goal to hold spheres at flat or curved interfaces, each with arbitrarily high energy potential weightings to mimic previously described features of particle packings on surfaces [17][18][19]106 .…”

Section: Methodsmentioning

confidence: 99%

“…During early branching morphogenesis, caps and stroma are both fluid-like on a developmental timescale 6,32 (Note S3). However, together with an excess rate of new tip formation the stroma thins over E14-E18, which causes niches to pack closer together, conform in shape because of the confinement imposed by neighboring niches, and locally align with each other 16 . Similar geometric features are observed in confined packings of soft elastic spheres 28 or closely packed droplets in dense two-phase emulsions such as foams [33][34][35] .…”

Section: Crowding Of Ureteric Bud Tip Domains Creates Crystal-like Pa...mentioning

confidence: 99%

“…We recently found that mouse embryonic kidney niche geometry is partially predictable through physical modeling of tip repulsion and crowding 16 . Preliminary analysis of UB tip positions at the surface revealed different crystal-like packing geometries that were at least locally ordered.…”

Section: Introductionmentioning

confidence: 99%

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Tubule jamming in the developing mouse kidney creates cyclical mechanical stresses in nephron-forming niches

Viola

Liu

Prahl

et al. 2022

Preprint

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The kidney develops through elaboration of ureteric epithelial tubules (the future urinary collecting ducts), stroma, and nephron progenitors in the cap mesenchyme that surrounds each ureteric tip as they branch. Dynamic interactions between these tissues coordinate a balance between ureteric tip branching and nephron formation that sets nephron numbers for life, which impacts the probability 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 clock that synchronizes nephron formation and ureteric 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.

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Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Crowding Of Ureteric Bud Tip Domains Creates Crystal-like Pa...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tubule jamming in the developing mouse kidney creates cyclical mechanical stresses in nephron-forming niches

Viola

Liu

Prahl

et al. 2022

Preprint

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Rho/ROCK activity tunes cell compartment segregation and differentiation in nephron-forming niches

Viola,

Liu,

Huang

et al. 2023

Preprint

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Controlling the time and place of nephron formationin vitrowould improve nephron density and connectivity in next-generation kidney replacement tissues. Recent developments in kidney organoid technology have paved the way to achieving self-sustaining nephrogenic nichesin vitro. The physical and geometric structure of the niche are key control parameters in tissue engineering approaches. However, their relationship to nephron differentiation is unclear. Here we investigate the relationship between niche geometry, cell compartment mixing, and nephron differentiation by targeting the Rho/ROCK pathway, a master regulator of the actin cytoskeleton. We find that the ROCK inhibitor Y-27632 increases mixing between nephron progenitor and stromal compartments in native mouse embryonic kidney niches, and also increases nephrogenesis. Similar increases are also seen in reductionist mouse primary cell and human induced pluripotent stem cell (iPSC)-derived organoids perturbed by Y-27632, dependent on the presence of stromal cells. Our data indicate that niche organization is a determinant of nephron formation rate, bringing renewed focus to the spatial context of cell-cell interactions in kidney tissue engineering efforts.

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Nephron progenitors rhythmically alternate between renewal and differentiation phases that synchronize with kidney branching morphogenesis

Davis,

Grindel,

Viola

et al. 2023

Preprint

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The mammalian kidney achieves massive parallelization of function by exponentially duplicating nephron-forming niches during development. Each niche caps a tip of the ureteric bud epithelium (the future urinary collecting duct tree) as it undergoes branching morphogenesis, while nephron progenitors within niches balance self-renewal and differentiation to early nephron cells. Nephron formation rate approximately matches branching rate over a large fraction of mouse gestation, yet the nature of this apparent pace-maker is unknown. Here we correlate spatial transcriptomics data with branching ‘life-cycle’ to discover rhythmically alternating signatures of nephron progenitor differentiation and renewal across Wnt, retinoic acid (RA), Hippo-Yap and other pathways. We then reveal stark differences in progenitor renewal vs. differentiation rates depending on whether Yap is activated in- or out-of-phase with Wnt/β-catenin-induced differentiation of human stem-cell derived nephron progenitor organoids. Our data brings temporal resolution to the renewal vs. differentiation balance in the nephrogenic niche, and informs new strategies to achieve self-sustaining niches in synthetic human kidney tissues.

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The developing murine kidney actively negotiates geometric packing conflicts to avoid defects

Cited by 5 publications

References 68 publications

Tubule jamming in the developing mouse kidney creates cyclical mechanical stresses in nephron-forming niches

Tubule jamming in the developing mouse kidney creates cyclical mechanical stresses in nephron-forming niches

Rho/ROCK activity tunes cell compartment segregation and differentiation in nephron-forming niches

Nephron progenitors rhythmically alternate between renewal and differentiation phases that synchronize with kidney branching morphogenesis

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