| First Author | Kim YK | Year | 2017 |
| Journal | Stem Cells | Volume | 35 |
| Issue | 12 | Pages | 2366-2378 |
| PubMed ID | 28905451 | Mgi Jnum | J:254956 |
| Mgi Id | MGI:6103548 | Doi | 10.1002/stem.2707 |
| Citation | Kim YK, et al. (2017) Gene-Edited Human Kidney Organoids Reveal Mechanisms of Disease in Podocyte Development. Stem Cells 35(12):2366-2378 |
| abstractText | 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. Stem Cells 2017;35:2366-2378. |
