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Jamming of nephron-forming niches in the developing mouse kidney creates cyclical mechanical stresses

Nature Materials volume 23, pages 1582–1591 (2024)Cite this article

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Abstract

Urinary collecting tubules form during kidney embryogenesis through the branching of the ureteric bud epithelium. A travelling mesenchyme niche of nephron progenitor cells caps each branching ureteric bud tip. These ‘tip domain’ niches pack more closely over developmental time and their number relates to nephron endowment at birth. Yet, how the crowded tissue environment impacts niche number and cell decision-making remains unclear. Here, through experiments and mathematical modelling, we show that niche packing conforms to physical limitations imposed by kidney curvature. We relate packing geometries to rigidity theory to predict a stiffening transition starting at embryonic day 15 in the mouse, validated by micromechanical analysis. Using a method to estimate tip domain ‘ages’ relative to their most recent branch events, we find that new niches overcome mechanical resistance as they branch and displace neighbours. This creates rhythmic mechanical stress in the niche. These findings expand our understanding of kidney development and inform engineering strategies for synthetic regenerative tissues.

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Fig. 1: Kidney curvature imposes topological requirements on geometry of close-packed nephrogenic niches at UB epithelial tubule tips.
Fig. 2: Close packing of UB tip domains predicts a transition to rigidity over developmental time.
Fig. 3: Crowding of UB tip domains stiffens the nephrogenic niche over time, especially in close-packed regions.
Fig. 4: Domain size and stromal cell elongation and alignment at ribbon interfaces between domains is dependent on myosin II.
Fig. 5: Newly established tip domains experience anisotropic mechanical stress that decreases over each life cycle.
Fig. 6: Model for curvature and crowding contributions to nephrogenic niche packing and its effects on mechanics.

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Data availability

All data necessary to evaluate the conclusions of this study are presented in the paper and Supplementary Information. Raw image stacks are available upon request due to prohibitive file sizes. Source data are available via Github at https://github.com/ahug030/kidney_jamming.

Code availability

Code used to generate curvature and height maps, Voronoi networks and shape index data, and sphere packing simulations is available at https://github.com/ahug030/kidney_jamming.

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Acknowledgements

We thank the Hughes lab members Z. Gartner, C. Nelson and M. Little for discussions and advice. We are grateful to K. Bennett at the Molecular Pathology and Imaging Core, Gastroenterology Division, Penn Medicine for technical assistance with laser ablation studies; and D. Li and P. Janmey for access to and training on microindentation. We thank N. Lindström for sending the supplementary image files from ref. 22. This work was supported by the following: NIH F32 fellowship DK126385 and Penn Center for Soft & Living Matter fellowship (L.S.P.), the Predoctoral Training Program in Developmental Biology T32HD083185 (J.M.V.), National Science Foundation (NSF) Graduate Research Fellowship Program (GRFP; J.L., T.J.C., G.H.-L. and C.M.P.), NIH National Institute of Child Health and Human Development (NICHD) K25HD097288 (J.Z.), NIH NICHD R21HD112663 (J.Z.), NIH National Institute of General Medical Sciences (NIGMS) Maximizing Investigators’ Research Award (MIRA) R35GM133380 (A.J.H.), NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01DK132296 (A.J.H.) and NSF CAREER awards 2339278 (J.Z.) and 2047271 (A.J.H.).

Author information

Author notes

  1. These authors contributed equally: Louis S. Prahl, Jiageng Liu, John M. Viola.

Authors and Affiliations

  1. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA

    Louis S. Prahl, Jiageng Liu, John M. Viola, Aria Zheyuan Huang, Trevor J. Chan, Catherine M. Porter & Alex J. Hughes

  2. Center for Soft and Living Matter, University of Pennsylvania, Philadelphia, PA, USA

    Louis S. Prahl & Alex J. Hughes

  3. Bioengineering Graduate Group, University of Pennsylvania, Philadelphia, PA, USA

    Jiageng Liu, John M. Viola, Aria Zheyuan Huang, Trevor J. Chan, Catherine M. Porter & Alex J. Hughes

  4. Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA

    Gabriela Hayward-Lara & Alex J. Hughes

  5. Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA

    Chenjun Shi & Jitao Zhang

  6. Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA

    Alex J. Hughes

  7. Center for Precision Engineering for Health (CPE4H), University of Pennsylvania, Philadelphia, PA, USA

    Alex J. Hughes

  8. Materials Research Science and Engineering Center (MRSEC), University of Pennsylvania, Philadelphia, PA, USA

    Alex J. Hughes

  9. Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Alex J. Hughes

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Contributions

Conceptualization was by L.S.P., J.M.V., T.J.C. and A.J.H. Methodology was by L.S.P., J.L., J.M.V., A.H., T.J.C., G.H.-L., C.M.P., J.Z. and A.J.H. Software was by J.M.V., T.J.C., J.Z. and A.J.H. Formal analysis was by J.M.V., T.J.C., J.Z. and A.J.H. Investigation was by L.S.P., J.L., J.M.V., A.H., T.J.C., G.H.-L., C.M.P., C.S., J.Z. and A.J.H. Writing the original draught was by J.Z. and A.J.H. Reviewing and editing was by L.S.P., J.L., J.M.V., A.H., T.J.C., G.H.-L., C.M.P., J.Z. and A.J.H. Visualization was by L.S.P., J.M.V., T.J.C., G.H.-L., C.S., J.Z. and A.J.H. Supervision was by L.S.P., J.Z. and A.J.H. Project administration was by J.Z. and A.J.H.

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Correspondence to Alex J. Hughes.

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Competing interests

L.S.P., J.M.V., J.L., A.H., C.M.P. and A.J.H. are listed as co-inventors on a published University of Pennsylvania international patent (WO 2023/235828 A1) relating to mechanics of nephrogenesis.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–10, Video Captions 1–3, Notes 1–11 and references.

Reporting Summary

Supplementary Video 1

Coordination of UB tip branching morphogenesis and nephron formation.

Supplementary Video 2

Asynchronous tip branching disrupts crystal-packed regions of tip domains in silico.

Supplementary Video 3

Laser ablation causes rebound of cap mesenchyme and stroma between pairs of UB tips.

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Prahl, L.S., Liu, J., Viola, J.M. et al. Jamming of nephron-forming niches in the developing mouse kidney creates cyclical mechanical stresses. Nat. Mater. 23, 1582–1591 (2024). https://doi.org/10.1038/s41563-024-02019-3

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