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Podocytes derived from human pluripotent stem cells (hPSC-podocytes) have recently been generated in nephron-like kidney organoids, but the developmental stage of these cells and their capacity to reveal disease mechanisms remains unclear. Here, we show that hPSC-podocytes phenocopy mammalian podocytes at the capillary loop stage (CLS), recapitulating key features of ultrastructure, gene expression, and mutant phenotype. hPSC-podocytes in vitro progressively establish junction-rich basal membranes (nephrin+podocin+ZO-1+) and microvillus-rich apical membranes (podocalyxin+), similar to CLS podocytes in vivo. Ultrastructural, biophysical, and transcriptomic analysis of podocalyxin-knockout hPSCs and derived podocytes, generated using CRISPR\/Cas9, reveals defects in the assembly of microvilli and lateral spaces between developing podocytes, resulting in failed junctional migration. These defects are phenocopied in CLS glomeruli of podocalyxin-deficient mice, which cannot produce urine, thereby demonstrating that podocalyxin has a conserved and essential role in mammalian podocyte maturation. Defining the maturity of hPSC-podocytes and their capacity to reveal and recapitulate pathophysiological mechanisms establishes a powerful framework for studying human kidney disease and regeneration.<\/jats:p>","DOI":"10.1002\/stem.2707","type":"journal-article","created":{"date-parts":[[2017,9,14]],"date-time":"2017-09-14T08:58:39Z","timestamp":1505379519000},"page":"2366-2378","source":"Crossref","is-referenced-by-count":116,"title":["Gene-Edited Human Kidney Organoids Reveal Mechanisms of Disease in Podocyte Development"],"prefix":"10.1093","volume":"35","author":[{"given":"Yong Kyun","family":"Kim","sequence":"first","affiliation":[{"name":"a Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"b Kidney Research Institute, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"c Institute for Stem Cell and Regenerative Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"d Department of Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ido","family":"Refaeli","sequence":"additional","affiliation":[{"name":"e The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada"},{"name":"f Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig R.","family":"Brooks","sequence":"additional","affiliation":[{"name":"g Division of Nephrology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peifeng","family":"Jing","sequence":"additional","affiliation":[{"name":"h Department of Electrical Engineering, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramila E.","family":"Gulieva","sequence":"additional","affiliation":[{"name":"a Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"b Kidney Research Institute, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"c Institute for Stem Cell and Regenerative Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"d Department of Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Hughes","sequence":"additional","affiliation":[{"name":"e The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada"},{"name":"f Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelly M.","family":"Cruz","sequence":"additional","affiliation":[{"name":"a Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"b Kidney Research Institute, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"c Institute for Stem Cell and Regenerative Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"d Department of Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannan","family":"Liu","sequence":"additional","affiliation":[{"name":"h Department of Electrical Engineering, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela J.","family":"Churchill","sequence":"additional","affiliation":[{"name":"a Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"b Kidney Research Institute, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"c Institute for Stem Cell and Regenerative Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"d Department of Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuliang","family":"Wang","sequence":"additional","affiliation":[{"name":"c Institute for Stem Cell and Regenerative Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"i Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxia","family":"Fu","sequence":"additional","affiliation":[{"name":"c Institute for Stem Cell and Regenerative Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"d Department of Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"j Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"k Department of Bioengineering, University of Washington School of Medicine, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey W.","family":"Pippin","sequence":"additional","affiliation":[{"name":"a Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"d Department of Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lih Y.","family":"Lin","sequence":"additional","affiliation":[{"name":"h Department of Electrical Engineering, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart J.","family":"Shankland","sequence":"additional","affiliation":[{"name":"a Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"d Department of Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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