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

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Publicado en:Nature Communications vol. 6 (Oct 2015), p. 8715-8727
Autor principal: Freedman, Benjamin S
Otros Autores: Brooks, Craig R, Lam, Albert Q, Fu, Hongxia, Morizane, Ryuji, Agrawal, Vishesh, Saad, Abdelaziz F, Li, Michelle K, Hughes, Michael R, Werff, Ryan Vander, Peters, Derek T, Lu, Junjie, Baccei, Anna, Siedlecki, Andrew M, Valerius, M Todd, Musunuru, Kiran, Mcnagny, Kelly M, Steinman, Theodore I, Zhou, Jing, Lerou, Paul H, Bonventre, Joseph V
Publicado:
Nature Publishing Group
Materias:
Harvard University Brigham & Womens Hospital University of Washington Harvard Medical School
United States > US
Massachusetts
Physiology
Embryos
CRISPR
Regenerative medicine
Kidney diseases
Genetic engineering
Hospitals
Stem cells
Medical schools
Cell culture
Nephrology
Kidneys
Social
Acceso en línea:Citation/Abstract
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Resumen: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.
ISSN:2041-1723
DOI:10.1038/ncomms9715
Fuente:Health & Medical Collection