Controlling nephron precursor differentiation to generate proximal-biased kidney organoids with emerging maturity.
Publication Year:
2025
PubMed ID:
40885711
Funding Grants:
Public Summary:
The kidney keeps the body’s fluid and chemical balance by filtering blood, reabsorbing important nutrients, and removing waste. A key part of this system—the proximal tubule—is especially vulnerable to injury, which can lead to serious kidney disease. Scientists can grow miniature kidney organoids from human stem cells to study development and disease, but these models typically don’t fully form mature proximal tubules.
In this study, researchers improved proximal tubule development by mimicking the signals that guide kidney formation in the body. By briefly blocking a pathway called PI3K early in development, they activated Notch signaling and pushed the organoids toward forming more mature proximal tubule cells. These enhanced organoids expressed the transport proteins needed for real kidney function. When exposed to toxins, they showed typical injury responses, including cell damage and activation of known kidney injury markers. Overall, these “proximal-biased” kidney organoids provide a more realistic model for studying kidney development, understanding injury, and testing new treatments.
Scientific 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.
