Cystic renal-epithelial derived induced pluripotent stem cells from polycystic kidney disease patients.

Autor: Kenter AT; Department of Developmental Biology, Erasmus Medical Center Rotterdam (EMC), Oncode Institute, Rotterdam, The Netherlands.; Department of Cell Biology, Erasmus Medical Center Rotterdam (EMC), Rotterdam, The Netherlands.; Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center Rotterdam (EMC), Rotterdam, The Netherlands., Rentmeester E; Department of Developmental Biology, Erasmus Medical Center Rotterdam (EMC), Oncode Institute, Rotterdam, The Netherlands., van Riet J; Cancer Computational Biology Center, Erasmus Medical Center Rotterdam (EMC), Rotterdam, The Netherlands., Boers R; Department of Developmental Biology, Erasmus Medical Center Rotterdam (EMC), Oncode Institute, Rotterdam, The Netherlands., Boers J; Department of Developmental Biology, Erasmus Medical Center Rotterdam (EMC), Oncode Institute, Rotterdam, The Netherlands.; Delft Diagnostic Laboratories (DDL), Rijswijk, The Netherlands., Ghazvini M; Department of Developmental Biology, Erasmus Medical Center Rotterdam (EMC), Oncode Institute, Rotterdam, The Netherlands., Xavier VJ; Department of Developmental Biology, Erasmus Medical Center Rotterdam (EMC), Oncode Institute, Rotterdam, The Netherlands., van Leenders GJLH; Department of Pathology, Erasmus Medical Center Rotterdam (EMC), Rotterdam, The Netherlands., Verhagen PCMS; Department of Urology, Erasmus Medical Center Rotterdam (EMC), Rotterdam, The Netherlands., van Til ME; Department of Clinical Genetics, Erasmus Medical Center Rotterdam (EMC), Rotterdam, The Netherlands., Eussen B; Department of Clinical Genetics, Erasmus Medical Center Rotterdam (EMC), Rotterdam, The Netherlands., Losekoot M; Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands., de Klein A; Department of Clinical Genetics, Erasmus Medical Center Rotterdam (EMC), Rotterdam, The Netherlands., Peters DJM; Department of Human Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands., van IJcken WFJ; Erasmus Center for Biomics, Erasmus Medical Center Rotterdam (EMC), Rotterdam, The Netherlands., van de Werken HJG; Cancer Computational Biology Center, Erasmus Medical Center Rotterdam (EMC), Rotterdam, The Netherlands., Zietse R; Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center Rotterdam (EMC), Rotterdam, The Netherlands., Hoorn EJ; Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center Rotterdam (EMC), Rotterdam, The Netherlands., Jansen G; Department of Cell Biology, Erasmus Medical Center Rotterdam (EMC), Rotterdam, The Netherlands., Gribnau JH; Department of Developmental Biology, Erasmus Medical Center Rotterdam (EMC), Oncode Institute, Rotterdam, The Netherlands.
Jazyk: angličtina
Zdroj: Stem cells translational medicine [Stem Cells Transl Med] 2020 Apr; Vol. 9 (4), pp. 478-490. Date of Electronic Publication: 2020 Mar 12.
DOI: 10.1002/sctm.18-0283
Abstrakt: Autosomal-dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, leading to kidney failure in most patients. In approximately 85% of cases, the disease is caused by mutations in PKD1. How dysregulation of PKD1 leads to cyst formation on a molecular level is unknown. Induced pluripotent stem cells (iPSCs) are a powerful tool for in vitro modeling of genetic disorders. Here, we established ADPKD patient-specific iPSCs to study the function of PKD1 in kidney development and cyst formation in vitro. Somatic mutations are proposed to be the initiating event of cyst formation, and therefore, iPSCs were derived from cystic renal epithelial cells rather than fibroblasts. Mutation analysis of the ADPKD iPSCs revealed germline mutations in PKD1 but no additional somatic mutations in PKD1/PKD2. Although several somatic mutations in other genes implicated in ADPKD were identified in cystic renal epithelial cells, only few of these mutations were present in iPSCs, indicating a heterogeneous mutational landscape, and possibly in vitro cell selection before and during the reprogramming process. Whole-genome DNA methylation analysis indicated that iPSCs derived from renal epithelial cells maintain a kidney-specific DNA methylation memory. In addition, comparison of PKD1+/- and control iPSCs revealed differences in DNA methylation associated with the disease history. In conclusion, we generated and characterized iPSCs derived from cystic and healthy control renal epithelial cells, which can be used for in vitro modeling of kidney development in general and cystogenesis in particular.
(© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)
Databáze: MEDLINE
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