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

Lorna J. Hale, Sara E. Howden, Belinda Phipson, Andrew Lonsdale, Pei X. Er, Irene Ghobrial, Salman Hosawi, Sean Wilson, Kynan T. Lawlor, Shahnaz Khan, Alicia Oshlack, Catherine Quinlan, Rachel Lennon and Melissa H. Little ()
Additional contact information
Lorna J. Hale: Murdoch Children’s Research Institute
Sara E. Howden: Murdoch Children’s Research Institute
Belinda Phipson: Murdoch Children’s Research Institute
Andrew Lonsdale: Murdoch Children’s Research Institute
Pei X. Er: Murdoch Children’s Research Institute
Irene Ghobrial: Murdoch Children’s Research Institute
Salman Hosawi: University of Manchester
Sean Wilson: Murdoch Children’s Research Institute
Kynan T. Lawlor: Murdoch Children’s Research Institute
Shahnaz Khan: Murdoch Children’s Research Institute
Alicia Oshlack: Murdoch Children’s Research Institute
Catherine Quinlan: Murdoch Children’s Research Institute
Rachel Lennon: University of Manchester
Melissa H. Little: Murdoch Children’s Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07594-z

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