Spatiotemporal dynamics and heterogeneity of renal lymphatics in mammalian development and cystic kidney disease

  1. Daniyal J Jafree
  2. Dale Moulding
  3. Maria Kolatsi-Joannou
  4. Nuria Perretta Tejedor
  5. Karen L Price
  6. Natalie J Milmoe
  7. Claire L Walsh
  8. Rosa Maria Correra
  9. Paul JD Winyard
  10. Peter C Harris
  11. Christiana Ruhrberg
  12. Simon Walker-Samuel
  13. Paul R Riley
  14. Adrian S Woolf
  15. Peter Scambler
  16. David A Long  Is a corresponding author
  1. University College London, United Kingdom
  2. Mayo Clinic, United States
  3. University of Oxford, United Kingdom
  4. University of Manchester, United Kingdom

Abstract

Heterogeneity of lymphatic vessels during embryogenesis is critical for organ-specific lymphatic function. Little is known about lymphatics in the developing kidney, despite their established roles in pathology of the mature organ. We performed three-dimensional imaging to characterize lymphatic vessel formation in the mammalian embryonic kidney at single-cell resolution. In mouse, we visually and quantitatively assessed the development of kidney lymphatic vessels, remodeling from a ring-like anastomosis under the nascent renal pelvis, a site of VEGF-C expression, to form a patent vascular plexus. We identified a heterogenous population of lymphatic endothelial cell clusters in mouse and human embryonic kidneys. Exogenous VEGF-C expanded the lymphatic population in explanted mouse embryonic kidneys. Finally, we characterized complex kidney lymphatic abnormalities in a genetic mouse model of polycystic kidney disease. Our study provides novel insights into the development of kidney lymphatic vasculature; a system which likely has fundamental roles in renal development, physiology and disease.

Data availability

The FIJI script used for segmenting and binarizing PROX1+/LYVE1+ cells has been provided as Source code file 1. All raw numerical data and results of statistical tests are attached as Source Data files with the appropriate figure.

Article and author information

Author details

  1. Daniyal J Jafree

    Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8235-0394
  2. Dale Moulding

    Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Maria Kolatsi-Joannou

    Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Nuria Perretta Tejedor

    Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Karen L Price

    Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Natalie J Milmoe

    Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Claire L Walsh

    Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Rosa Maria Correra

    UCL Institute of Ophthalmology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Paul JD Winyard

    Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Peter C Harris

    Division of Nephrology and Hypertension, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Christiana Ruhrberg

    UCL Institute of Ophthalmology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Simon Walker-Samuel

    Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Paul R Riley

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9862-7332
  14. Adrian S Woolf

    School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5541-1358
  15. Peter Scambler

    Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. David A Long

    Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
    For correspondence
    d.long@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6580-3435

Funding

UCL Great Ormond Street Institute of Child Health (Child Health Research Studentship)

  • Daniyal J Jafree
  • Peter Scambler
  • David A Long

British Heart Foundation (RG/15/14/31880)

  • Peter Scambler

Kidney Research UK (Paed_RP_10_2018)

  • Daniyal J Jafree
  • Adrian S Woolf
  • David A Long

Kidney Research UK (IN_012_2019)

  • Daniyal J Jafree
  • David A Long

University College London MB/PhD Programme (MB/PhD Studentship)

  • Daniyal J Jafree

Medical Research Council (MR/P018629/1)

  • David A Long

Medical Research Council (MR/L002744/1)

  • Adrian S Woolf

Medical Research Council (MR/K026739/1)

  • Adrian S Woolf

British Heart Foundation (FS/19/14/34170)

  • Rosa Maria Correra

Diabetes UK (15/0005283)

  • David A Long

NIHR Great Ormond Street Hospital Biomedical Research Centre Award (17DD08)

  • Dale Moulding

British Heart Foundation (CH/11/1/28798)

  • Paul R Riley

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were carried out according to a UK Home Office project license (PPL: PE52D8C09) and were compliant with the UK Animals (Scientific Procedures) Act 1986.

Human subjects: Human fetal kidneys were obtained from the Human Developmental Biology Resource (http://www.hdbr.org), which obtains written consent from donors to collect, store and distribute human fetal material between 4-20PCW.

Reviewing Editor

  1. Kari Alitalo, Wihuri Research Institute, Finland

Publication history

  1. Received: May 3, 2019
  2. Accepted: November 30, 2019
  3. Accepted Manuscript published: December 6, 2019 (version 1)
  4. Version of Record published: January 8, 2020 (version 2)

Copyright

© 2019, Jafree et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Daniyal J Jafree
  2. Dale Moulding
  3. Maria Kolatsi-Joannou
  4. Nuria Perretta Tejedor
  5. Karen L Price
  6. Natalie J Milmoe
  7. Claire L Walsh
  8. Rosa Maria Correra
  9. Paul JD Winyard
  10. Peter C Harris
  11. Christiana Ruhrberg
  12. Simon Walker-Samuel
  13. Paul R Riley
  14. Adrian S Woolf
  15. Peter Scambler
  16. David A Long
(2019)
Spatiotemporal dynamics and heterogeneity of renal lymphatics in mammalian development and cystic kidney disease
eLife 8:e48183.
https://doi.org/10.7554/eLife.48183
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