TY - JOUR
T1 - Adult human kidney organoids originate from CD24+ cells and represent an advanced model for adult polycystic kidney disease
AU - Xu, Yaoxian
AU - Kuppe, Christoph
AU - Perales-Patón, Javier
AU - Hayat, Sikander
AU - Kranz, Jennifer
AU - Abdallah, Ali T.
AU - Nagai, James
AU - Li, Zhijian
AU - Peisker, Fabian
AU - Saritas, Turgay
AU - Halder, Maurice
AU - Menzel, Sylvia
AU - Hoeft, Konrad
AU - Kenter, Annegien
AU - Kim, Hyojin
AU - van Roeyen, Claudia R.C.
AU - Lehrke, Michael
AU - Moellmann, Julia
AU - Speer, Thimoteus
AU - Buhl, Eva M.
AU - Hoogenboezem, Remco
AU - Boor, Peter
AU - Jansen, Jitske
AU - Knopp, Cordula
AU - Kurth, Ingo
AU - Smeets, Bart
AU - Bindels, Eric
AU - Reinders, Marlies E.J.
AU - Baan, Carla
AU - Gribnau, Joost
AU - Hoorn, Ewout J.
AU - Steffens, Joachim
AU - Huber, Tobias B.
AU - Costa, Ivan
AU - Floege, Jürgen
AU - Schneider, Rebekka K.
AU - Saez-Rodriguez, Julio
AU - Freedman, Benjamin S.
AU - Kramann, Rafael
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85140914652&partnerID=8YFLogxK
U2 - 10.1038/s41588-022-01202-z
DO - 10.1038/s41588-022-01202-z
M3 - Article
C2 - 36303074
AN - SCOPUS:85140914652
VL - 54
SP - 1690
EP - 1701
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 11
ER -
