Controlling nephron precursor differentiation to generate proximal-biased kidney organoids with emerging maturity

Jack Schnell, Zhen Miao, MaryAnne Achieng, Connor C. Fausto, Kari Koppitch, Lola Takhirov, Victoria Wang, Faith De Kuyper, Biao Huang, Megan Schreiber, Pedro Medina, Matthew E. Thornton, Brendan Grubbs, Zhongwei Li, Junhyong Kim and Nils O. Lindström ()
Additional contact information
Jack Schnell: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at University of Southern California
Zhen Miao: University of Pennsylvania
MaryAnne Achieng: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at University of Southern California
Connor C. Fausto: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at University of Southern California
Kari Koppitch: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at University of Southern California
Lola Takhirov: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at University of Southern California
Victoria Wang: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at University of Southern California
Faith De Kuyper: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at University of Southern California
Biao Huang: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at University of Southern California
Megan Schreiber: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at University of Southern California
Pedro Medina: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at University of Southern California
Matthew E. Thornton: University of Southern California
Brendan Grubbs: University of Southern California
Zhongwei Li: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at University of Southern California
Junhyong Kim: University of Pennsylvania
Nils O. Lindström: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at University of Southern California

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract The kidney maintains fluid homeostasis by reabsorbing essential compounds and excreting waste. Proximal tubule cells, crucial for reabsorbing sugars, ions, and amino acids, are highly susceptible to injury, often leading to pathologies necessitating dialysis or transplants. Human pluripotent stem cell-derived kidney organoids offer a platform to model renal development, function, and disease, but proximal nephron differentiation and maturation in these structures is incomplete. Here, we drive proximal tubule development in pluripotent stem cell-derived kidney organoids by mimicking in vivo proximal differentiation. Transient PI3K inhibition during early nephrogenesis activates Notch signaling, shifting nephron axial differentiation towards epithelial and proximal precursor states that mature to proximal convoluted tubule cells broadly expressing physiology-imparting solute carriers including organic cation and organic anion family members. The “proximal-biased” organoids thus acquire function, and on exposure to nephrotoxic injury, display tubular collapse and DNA damage, and upregulate injury response markers HAVCR1/KIM1 and SOX9 while downregulating proximal transcription factor HNF4A. Here, we show that proximally biased human-derived kidney organoids provide a robust model to study nephron development, injury responses, and a platform for therapeutic discovery.

Date: 2025
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DOI: 10.1038/s41467-025-63107-9

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