Patterning human kidney organoids with synthetic Wnt-secreting organizers
4 affiliations
- 1Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at University of Southern California, Los Angeles, CA, USA
- 2Maternal Fetal Medicine Division, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- 3Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- 4Alfred E. Mann Department of Biomedical Engineering, USC Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA
Abstract
Current human pluripotent stem cell-derived kidney organoids contain nephron-like structures that lack organotypic patterning. It is thought that during human development, nephrons form their proximal-distal axial polarity in response to collecting duct-derived signals that are absent in kidney organoids. To delineate how nephron polarities establish, we profiled human kidney development by spatial transcriptomic approaches. Our analyses describe a new axial polarity in the nephron and demonstrate that the nephron proximal-distal polarity develops adjacent to a transcriptional boundary in the collecting duct where non-canonical WNT11 is downregulated and canonical WNT9B ligand is upregulated. The nephron region closest to this boundary in turn activates a series of canonical WNT target genes inferring positional nephron identities. To establish whether a canonical WNT source can improve organoid patterning to an in vivo -like state, we bioengineered self-organizing WNT-secreting synthetic organizers. Organizer-coupled kidney organoids respond to WNT ligands by forming expression gradients and developing distal cell identities. Tuning the WNT dose produced nephrons with continuous patterning along the proximal-distal axis. Strikingly, polarized iPSC-derived nephrons directed their distal tubules towards the WNT-source, indicating axial patterning and morphogenetic programs are tuned by WNTs from the synthetic organizers. Our data present a strategy to control organ patterning, build an artificial kidney, and highlights the power of synthetic organizer systems for advancing organoid models.
Related
- Stochasticity in response to rostrocaudal and mediolateral determinants influences inaccurate specification within kidney organoids.
- Anti-PD-L1 scFv-secreting fifth-generation GD2-CAR T cells enhance antitumor function against GD2-low retinoblastoma
- Editorial: Patterning mechanisms in cardiovascular dysfunction: from bench to bedside
- Consecutive waves of NODAL inhibition are required for epiblast patterning
- Multiscale spatial analysis implicates chromosomal metaloops in gene patterning across the Drosophila brain
BibTeX
@article{fausto2026patterning,
title = {{Patterning human kidney organoids with synthetic Wnt-secreting organizers}},
author = {Connor C. Fausto and Fokion Glykofrydis and Navneet Kumar and Jack Schnell and Réka L. Csipán and Faith De Kuyper and Minnal Kunnan and Brendan H. Grubbs and Matthew Edward Thornton and Michael Thompson and Enmian Chang and Xuduo Wen and Manuel Pelayo and MaryAnne A. Achieng and Anoothi Seth and Kelly Street and Leonardo Morsut and Nils O. Lindström},
journal = {Science},
year = {2026},
month = jul,
doi = {10.1126/science.adu9122},
url = {https://doi.org/10.1126/science.adu9122},
note = {CC BY},
}
RIS
TY - JOUR
TI - Patterning human kidney organoids with synthetic Wnt-secreting organizers
AU - Connor C. Fausto
AU - Fokion Glykofrydis
AU - Navneet Kumar
AU - Jack Schnell
AU - Réka L. Csipán
AU - Faith De Kuyper
AU - Minnal Kunnan
AU - Brendan H. Grubbs
AU - Matthew Edward Thornton
AU - Michael Thompson
AU - Enmian Chang
AU - Xuduo Wen
AU - Manuel Pelayo
AU - MaryAnne A. Achieng
AU - Anoothi Seth
AU - Kelly Street
AU - Leonardo Morsut
AU - Nils O. Lindström
PY - 2026
DA - 2026/07/02
JO - Science
DO - 10.1126/science.adu9122
UR - https://doi.org/10.1126/science.adu9122
AB - Current human pluripotent stem cell-derived kidney organoids contain nephron-like structures that lack organotypic patterning. It is thought that during human development, nephrons form their proximal-distal axial polarity in response to collecting duct-derived signals that are absent in kidney organoids. To delineate how nephron polarities establish, we profiled human kidney development by spatial transcriptomic approaches. Our analyses describe a new axial polarity in the nephron and demonstrate that the nephron proximal-distal polarity develops adjacent to a transcriptional boundary in the collecting duct where non-canonical WNT11 is downregulated and canonical WNT9B ligand is upregulated. The nephron region closest to this boundary in turn activates a series of canonical WNT target genes inferring positional nephron identities. To establish whether a canonical WNT source can improve organoid patterning to an in vivo -like state, we bioengineered self-organizing WNT-secreting synthetic organizers. Organizer-coupled kidney organoids respond to WNT ligands by forming expression gradients and developing distal cell identities. Tuning the WNT dose produced nephrons with continuous patterning along the proximal-distal axis. Strikingly, polarized iPSC-derived nephrons directed their distal tubules towards the WNT-source, indicating axial patterning and morphogenetic programs are tuned by WNTs from the synthetic organizers. Our data present a strategy to control organ patterning, build an artificial kidney, and highlights the power of synthetic organizer systems for advancing organoid models.
SN - 0036-8075
SN - 0193-4511
SN - 1095-9203
ER -