Adult human kidney organoids originate from CD24+ cells and represent an advanced model for adult polycystic kidney disease

Yaoxian Xu, Christoph Kuppe, Javier Perales-Patón, Sikander Hayat, Jennifer Kranz, Ali T. Abdallah, James Nagai, Zhijian Li, Fabian Peisker, Turgay Saritas, Maurice Halder, Sylvia Menzel, Konrad Hoeft, Annegien Kenter, Hyojin Kim, Claudia R.C. van Roeyen, Michael Lehrke, Julia Moellmann, Thimoteus Speer, Eva M. BuhlRemco Hoogenboezem, Peter Boor, Jitske Jansen, Cordula Knopp, Ingo Kurth, Bart Smeets, Eric Bindels, Marlies E.J. Reinders, Carla Baan, Joost Gribnau, Ewout J. Hoorn, Joachim Steffens, Tobias B. Huber, Ivan Costa, Jürgen Floege, Rebekka K. Schneider, Julio Saez-Rodriguez, Benjamin S. Freedman, Rafael Kramann*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

Adult kidney organoids have been described as strictly tubular epithelia and termed tubuloids. While the cellular origin of tubuloids has remained elusive, here we report that they originate from a distinct CD24+ epithelial subpopulation. Long-term-cultured CD24+ cell-derived tubuloids represent a functional human kidney tubule. We show that kidney tubuloids can be used to model the most common inherited kidney disease, namely autosomal dominant polycystic kidney disease (ADPKD), reconstituting the phenotypic hallmark of this disease with cyst formation. Single-cell RNA sequencing of CRISPR–Cas9 gene-edited PKD1- and PKD2-knockout tubuloids and human ADPKD and control tissue shows similarities in upregulation of disease-driving genes. Furthermore, in a proof of concept, we demonstrate that tolvaptan, the only approved drug for ADPKD, has a significant effect on cyst size in tubuloids but no effect on a pluripotent stem cell-derived model. Thus, tubuloids are derived from a tubular epithelial subpopulation and represent an advanced system for ADPKD disease modeling.

Original languageEnglish
Pages (from-to)1690-1701
Number of pages12
JournalNature Genetics
Volume54
Issue number11
DOIs
Publication statusPublished - Nov 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

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