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Modelling renal defects in Bardet-Biedl syndrome patients using human iPS cells

Williams, James; Hurling, Chloe; Munir, Sabrina; Harley, Peter; Machado, Carolina Barcellos; Cujba, Ana-Maria; Alvarez-Fallas, Mario; ... Watt, Fiona M; + view all (2023) Modelling renal defects in Bardet-Biedl syndrome patients using human iPS cells. Frontiers in Cell and Developmental Biology , 11 , Article 1163825. 10.3389/fcell.2023.1163825. Green open access

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Abstract

Bardet-Biedl syndrome (BBS) is a ciliopathy with pleiotropic effects on multiple tissues, including the kidney. Here we have compared renal differentiation of iPS cells from healthy and BBS donors. High content image analysis of WT1-expressing kidney progenitors showed that cell proliferation, differentiation and cell shape were similar in healthy, BBS1, BBS2, and BBS10 mutant lines. We then examined three patient lines with BBS10 mutations in a 3D kidney organoid system. The line with the most deleterious mutation, with low BBS10 expression, expressed kidney marker genes but failed to generate 3D organoids. The other two patient lines expressed near normal levels of BBS10 mRNA and generated multiple kidney lineages within organoids when examined at day 20 of organoid differentiation. However, on prolonged culture (day 27) the proximal tubule compartment degenerated. Introducing wild type BBS10 into the most severely affected patient line restored organoid formation, whereas CRISPR-mediated generation of a truncating BBS10 mutation in a healthy line resulted in failure to generate organoids. Our findings provide a basis for further mechanistic studies of the role of BBS10 in the kidney.

Type: Article
Title: Modelling renal defects in Bardet-Biedl syndrome patients using human iPS cells
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fcell.2023.1163825
Publisher version: https://doi.org/10.3389/fcell.2023.1163825
Language: English
Additional information: Copyright © 2023 Williams, Hurling, Munir, Harley, Machado, Cujba, Alvarez-Fallas, Danovi, Lieberam, Sancho, Beales and Watt. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: iPSC (induced pluripotent stem cell), kidney, ciliopathy, CRISPR, Bardet-Biedl syndrome
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10171467
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