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3D organoid-derived human glomeruli for personalised podocyte disease modelling and drug screening

Author

Listed:
  • Lorna J. Hale

    (Murdoch Children’s Research Institute
    The University of Melbourne)

  • Sara E. Howden

    (Murdoch Children’s Research Institute
    The University of Melbourne)

  • Belinda Phipson

    (Murdoch Children’s Research Institute)

  • Andrew Lonsdale

    (Murdoch Children’s Research Institute)

  • Pei X. Er

    (Murdoch Children’s Research Institute)

  • Irene Ghobrial

    (Murdoch Children’s Research Institute)

  • Salman Hosawi

    (University of Manchester)

  • Sean Wilson

    (Murdoch Children’s Research Institute)

  • Kynan T. Lawlor

    (Murdoch Children’s Research Institute)

  • Shahnaz Khan

    (Murdoch Children’s Research Institute)

  • Alicia Oshlack

    (Murdoch Children’s Research Institute
    The University of Melbourne)

  • Catherine Quinlan

    (Murdoch Children’s Research Institute
    The University of Melbourne
    Royal Children’s Hospital)

  • Rachel Lennon

    (University of Manchester)

  • Melissa H. Little

    (Murdoch Children’s Research Institute
    The University of Melbourne)

Abstract

The podocytes within the glomeruli of the kidney maintain the filtration barrier by forming interdigitating foot processes with intervening slit diaphragms, disruption in which results in proteinuria. Studies into human podocytopathies to date have employed primary or immortalised podocyte cell lines cultured in 2D. Here we compare 3D human glomeruli sieved from induced pluripotent stem cell-derived kidney organoids with conditionally immortalised human podocyte cell lines, revealing improved podocyte-specific gene expression, maintenance in vitro of polarised protein localisation and an improved glomerular basement membrane matrisome compared to 2D cultures. Organoid-derived glomeruli retain marker expression in culture for 96 h, proving amenable to toxicity screening. In addition, 3D organoid glomeruli from a congenital nephrotic syndrome patient with compound heterozygous NPHS1 mutations reveal reduced protein levels of both NEPHRIN and PODOCIN. Hence, human iPSC-derived organoid glomeruli represent an accessible approach to the in vitro modelling of human podocytopathies and screening for podocyte toxicity.

Suggested Citation

  • Lorna J. Hale & Sara E. Howden & Belinda Phipson & Andrew Lonsdale & Pei X. Er & Irene Ghobrial & Salman Hosawi & Sean Wilson & Kynan T. Lawlor & Shahnaz Khan & Alicia Oshlack & Catherine Quinlan & Ra, 2018. "3D organoid-derived human glomeruli for personalised podocyte disease modelling and drug screening," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07594-z
    DOI: 10.1038/s41467-018-07594-z
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    Cited by:

    1. Jessica M. Vanslambrouck & Sean B. Wilson & Ker Sin Tan & Ella Groenewegen & Rajeev Rudraraju & Jessica Neil & Kynan T. Lawlor & Sophia Mah & Michelle Scurr & Sara E. Howden & Kanta Subbarao & Melissa, 2022. "Enhanced metanephric specification to functional proximal tubule enables toxicity screening and infectious disease modelling in kidney organoids," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    2. Moritz Lassé & Jamal El Saghir & Celine C. Berthier & Sean Eddy & Matthew Fischer & Sandra D. Laufer & Dominik Kylies & Arvid Hutzfeldt & Léna Lydie Bonin & Bernhard Dumoulin & Rajasree Menon & Virgin, 2023. "An integrated organoid omics map extends modeling potential of kidney disease," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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