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Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids

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  • Benjamin S. Freedman

    (Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine
    University of Washington School of Medicine
    Kidney Research Institute, University of Washington
    Institute for Stem Cell and Regenerative Medicine, University of Washington)

  • Craig R. Brooks

    (Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine)

  • Albert Q. Lam

    (Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine
    Harvard Stem Cell Institute, Harvard University)

  • Hongxia Fu

    (Boston Children’s Hospital, Center for Life Sciences, Harvard Medical School)

  • Ryuji Morizane

    (Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine)

  • Vishesh Agrawal

    (Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine
    Brigham and Women’s Hospital, Harvard Medical School)

  • Abdelaziz F. Saad

    (Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine)

  • Michelle K. Li

    (Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine
    Harvard University)

  • Michael R. Hughes

    (The Biomedical Research Centre, University of British Columbia)

  • Ryan Vander Werff

    (The Biomedical Research Centre, University of British Columbia)

  • Derek T. Peters

    (Harvard University
    Brigham and Women’s Hospital, Harvard Medical School)

  • Junjie Lu

    (Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine
    Brigham and Women’s Hospital, Harvard Medical School)

  • Anna Baccei

    (Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine
    Brigham and Women’s Hospital, Harvard Medical School)

  • Andrew M. Siedlecki

    (Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine)

  • M. Todd Valerius

    (Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine
    Harvard Stem Cell Institute, Harvard University)

  • Kiran Musunuru

    (Harvard University
    Brigham and Women’s Hospital, Harvard Medical School)

  • Kelly M. McNagny

    (The Biomedical Research Centre, University of British Columbia)

  • Theodore I. Steinman

    (Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine
    Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Jing Zhou

    (Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine
    Harvard Stem Cell Institute, Harvard University)

  • Paul H. Lerou

    (Harvard Stem Cell Institute, Harvard University
    Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine
    Brigham and Women’s Hospital, Harvard Medical School)

  • Joseph V. Bonventre

    (Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine
    Harvard Stem Cell Institute, Harvard University)

Abstract

Human-pluripotent-stem-cell-derived kidney cells (hPSC-KCs) have important potential for disease modelling and regeneration. Whether the hPSC-KCs can reconstitute tissue-specific phenotypes is currently unknown. Here we show that hPSC-KCs self-organize into kidney organoids that functionally recapitulate tissue-specific epithelial physiology, including disease phenotypes after genome editing. In three-dimensional cultures, epiblast-stage hPSCs form spheroids surrounding hollow, amniotic-like cavities. GSK3β inhibition differentiates spheroids into segmented, nephron-like kidney organoids containing cell populations with characteristics of proximal tubules, podocytes and endothelium. Tubules accumulate dextran and methotrexate transport cargoes, and express kidney injury molecule-1 after nephrotoxic chemical injury. CRISPR/Cas9 knockout of podocalyxin causes junctional organization defects in podocyte-like cells. Knockout of the polycystic kidney disease genes PKD1 or PKD2 induces cyst formation from kidney tubules. All of these functional phenotypes are distinct from effects in epiblast spheroids, indicating that they are tissue specific. Our findings establish a reproducible, versatile three-dimensional framework for human epithelial disease modelling and regenerative medicine applications.

Suggested Citation

  • Benjamin S. Freedman & Craig R. Brooks & Albert Q. Lam & Hongxia Fu & Ryuji Morizane & Vishesh Agrawal & Abdelaziz F. Saad & Michelle K. Li & Michael R. Hughes & Ryan Vander Werff & Derek T. Peters & , 2015. "Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids," Nature Communications, Nature, vol. 6(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9715
    DOI: 10.1038/ncomms9715
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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. Dohui Kim & Hyeonji Lim & Jaeseung Youn & Tae-Eun Park & Dong Sung Kim, 2024. "Scalable production of uniform and mature organoids in a 3D geometrically-engineered permeable membrane," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Sienna R. Li & Ramila E. Gulieva & Louisa Helms & Nelly M. Cruz & Thomas Vincent & Hongxia Fu & Jonathan Himmelfarb & Benjamin S. Freedman, 2022. "Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. 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.
    5. J. O. R. Hernandez & X. Wang & M. Vazquez-Segoviano & M. Lopez-Marfil & M. F. Sobral-Reyes & A. Moran-Horowich & M. Sundberg & D. O. Lopez-Cantu & C. K. Probst & G. U. Ruiz-Esparza & K. Giannikou & R., 2021. "A tissue-bioengineering strategy for modeling rare human kidney diseases in vivo," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

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