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

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, Junjie Lu, Anna Baccei, Andrew M. Siedlecki, M. Todd Valerius, Kiran Musunuru, Kelly M. McNagny, Theodore I. Steinman, Jing Zhou, Paul H. Lerou and Joseph V. Bonventre
Additional contact information
Benjamin S. Freedman: Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine
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
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
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
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
Junjie Lu: Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine
Anna Baccei: Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine
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
Kiran Musunuru: Harvard University
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
Jing Zhou: Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine
Paul H. Lerou: Harvard Stem Cell Institute, Harvard University
Joseph V. Bonventre: Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9715

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