3D organoid-derived human glomeruli for personalised podocyte disease modelling and drug screening

Nat Commun. 2018 Dec 4;9(1):5167. doi: 10.1038/s41467-018-07594-z.

Abstract

The podocytes within the glomeruli of the kidney maintain the filtration barrier by forming interdigitating foot processes with intervening slit diaphragms, disruption in which results in proteinuria. Studies into human podocytopathies to date have employed primary or immortalised podocyte cell lines cultured in 2D. Here we compare 3D human glomeruli sieved from induced pluripotent stem cell-derived kidney organoids with conditionally immortalised human podocyte cell lines, revealing improved podocyte-specific gene expression, maintenance in vitro of polarised protein localisation and an improved glomerular basement membrane matrisome compared to 2D cultures. Organoid-derived glomeruli retain marker expression in culture for 96 h, proving amenable to toxicity screening. In addition, 3D organoid glomeruli from a congenital nephrotic syndrome patient with compound heterozygous NPHS1 mutations reveal reduced protein levels of both NEPHRIN and PODOCIN. Hence, human iPSC-derived organoid glomeruli represent an accessible approach to the in vitro modelling of human podocytopathies and screening for podocyte toxicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Culture Techniques / methods
  • Cell Line
  • Cells, Cultured
  • Collagen / metabolism
  • Drug Evaluation, Preclinical*
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Humans
  • Immunohistochemistry
  • Induced Pluripotent Stem Cells / cytology
  • Insulin / pharmacology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kidney
  • Kidney Glomerulus / cytology*
  • Laminin / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mutation
  • Nephrotic Syndrome / pathology
  • Organoids / cytology*
  • Organoids / drug effects
  • Podocytes / cytology*
  • Podocytes / drug effects
  • Sequence Analysis
  • Sequence Analysis, RNA
  • Stem Cells

Substances

  • Insulin
  • Intracellular Signaling Peptides and Proteins
  • Laminin
  • Membrane Proteins
  • NPHS2 protein
  • nephrin
  • Collagen

Supplementary concepts

  • Nephrosis, congenital