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

Annegien T Kenter1,2,3, Eveline Rentmeester1, Job van Riet4

  • 1Department of Developmental Biology, Erasmus Medical Center Rotterdam (EMC), Oncode Institute, Rotterdam, The Netherlands.

Stem Cells Translational Medicine
|March 13, 2020
PubMed

Insights

Autosomal-dominant polycystic kidney disease (ADPKD) research advances with patient-specific induced pluripotent stem cells (iPSCs). These iPSCs model PKD1 gene function in kidney cyst formation, offering new insights into disease mechanisms.

Area of Science:

  • Nephrology
  • Genetics
  • Stem Cell Biology

Background:

  • Autosomal-dominant polycystic kidney disease (ADPKD) is the most prevalent inherited kidney disorder, frequently resulting in kidney failure.
  • Mutations in the PKD1 gene account for approximately 85% of ADPKD cases, yet the molecular mechanisms of cystogenesis remain unclear.
  • Induced pluripotent stem cells (iPSCs) offer a valuable platform for in vitro modeling of genetic kidney diseases.

Purpose of the Study:

  • To establish and characterize ADPKD patient-specific iPSCs for studying PKD1 function in kidney development and cyst formation.
  • To investigate the role of somatic mutations and DNA methylation in ADPKD pathogenesis using iPSCs derived from renal epithelial cells.

Main Methods:

  • Generation of iPSCs from ADPKD patient-derived cystic renal epithelial cells and healthy controls.
  • Comprehensive mutation analysis of PKD1, PKD2, and other ADPKD-associated genes in iPSCs.
  • Whole-genome DNA methylation analysis to assess kidney-specific epigenetic memory and disease-associated alterations.

Main Results:

  • ADPKD patient-specific iPSCs were successfully generated, harboring germline PKD1 mutations but lacking additional somatic mutations in PKD1/PKD2.
  • Analysis revealed a heterogeneous mutational landscape in the original cystic cells, with limited carryover of somatic mutations into iPSCs.
  • iPSCs derived from renal epithelial cells retained kidney-specific DNA methylation patterns, with distinct methylation differences observed in PKD1+/- iPSCs compared to controls.

Conclusions:

  • Generated and characterized ADPKD patient-specific iPSCs provide a robust in vitro model for studying kidney development and cystogenesis.
  • These iPSCs can be utilized to investigate the molecular mechanisms underlying PKD1 dysregulation in ADPKD.
  • The findings highlight the potential of iPSCs in understanding inherited kidney diseases and exploring therapeutic strategies.

Keywords:
ADPKDDNA methylationPKD1cystepigenetic memoryiPS cellsrenal epithelial cellssecond hitsomatic mutation

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