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Enhanced metanephric specification to functional proximal tubule enables toxicity screening and infectious disease modelling in kidney organoids

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  • Jessica M. Vanslambrouck

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

  • Sean B. Wilson

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

  • Ker Sin Tan

    (Murdoch Children’s Research Institute)

  • Ella Groenewegen

    (Murdoch Children’s Research Institute)

  • Rajeev Rudraraju

    (The University of Melbourne)

  • Jessica Neil

    (The University of Melbourne)

  • Kynan T. Lawlor

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

  • Sophia Mah

    (Murdoch Children’s Research Institute)

  • Michelle Scurr

    (Murdoch Children’s Research Institute)

  • Sara E. Howden

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

  • Kanta Subbarao

    (The University of Melbourne)

  • Melissa H. Little

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

Abstract

While pluripotent stem cell-derived kidney organoids are now being used to model renal disease, the proximal nephron remains immature with limited evidence for key functional solute channels. This may reflect early mispatterning of the nephrogenic mesenchyme and/or insufficient maturation. Here we show that enhanced specification to metanephric nephron progenitors results in elongated and radially aligned proximalised nephrons with distinct S1 - S3 proximal tubule cell types. Such PT-enhanced organoids possess improved albumin and organic cation uptake, appropriate KIM-1 upregulation in response to cisplatin, and improved expression of SARS-CoV-2 entry factors resulting in increased viral replication. The striking proximo-distal orientation of nephrons resulted from localized WNT antagonism originating from the organoid stromal core. PT-enhanced organoids represent an improved model to study inherited and acquired proximal tubular disease as well as drug and viral responses.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33623-z
    DOI: 10.1038/s41467-022-33623-z
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