دورية أكاديمية
Gene-Edited Human Kidney Organoids Reveal Mechanisms of Disease in Podocyte Development
| العنوان: | Gene-Edited Human Kidney Organoids Reveal Mechanisms of Disease in Podocyte Development |
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| المؤلفون: | Kim, Yong Kyun, Refaeli, Ido, Brooks, Craig R., Jing, Peifeng, Gulieva, Ramila E., Hughes, Michael R., Cruz, Nelly M., Liu, Yannan, Churchill, Angela J., Wang, Yuliang, Fu, Hongxia, Pippin, Jeffrey W., Lin, Lih Y., Shankland, Stuart J., Vogl, A. Wayne, McNagny, Kelly M., Freedman, Benjamin S. |
| المساهمون: | NIH National Institute of Diabetes and Digestive and Kidney Diseases, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Kidney Foundation Young Investigator Grant, American Society of Nephrology Carl W. Gottschalk Research Scholar Award, Natural Sciences and Engineering Research Council of Canada, Directorate for Biological Sciences, National Science Foundation, Northwest Kidney Centers to the Kidney Research Institute |
| المصدر: | Stem Cells ; volume 35, issue 12, page 2366-2378 ; ISSN 1066-5099 1549-4918 |
| بيانات النشر: | Oxford University Press (OUP) |
| سنة النشر: | 2017 |
| الوصف: | A critical event during kidney organogenesis is the differentiation of podocytes, specialized epithelial cells that filter blood plasma to form urine. 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1002/stem.2707 |
| الإتاحة: | https://doi.org/10.1002/stem.2707Test https://academic.oup.com/stmcls/article-pdf/35/12/2366/42604295/stmcls_35_12_2366.pdfTest |
| حقوق: | https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_modelTest |
| رقم الانضمام: | edsbas.D6543322 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1002/stem.2707 |
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