Article Impact Level: HIGH Data Quality: STRONG Summary of The EMBO Journal. https://doi.org/10.1038/s44318-025-00504-2 Dr. Michael Namestnikov et al.
Points
- Researchers developed a novel protocol to culture human fetal kidney-derived organoids from pure NCAM1+ progenitor cells, thereby bypassing the issues associated with pluripotent stem cell models.
- These advanced organoids demonstrate remarkable long-term stability and maturation for over six months, representing a significant improvement over the previous four-week lifespans of similar cultures.
- Single-cell sequencing confirmed the organoids faithfully model nephrogenesis by generating diverse renal cell types and maintaining a continuous pool of epithelial progenitors for development.
- Inhibiting the Notch signaling pathway revealed a critical maturation block in the organoids and identified a novel cell state, characterized by prominin-1 expression, that can bypass this inhibition.
- This breakthrough provides a powerful new tool for modeling kidney diseases, screening for fetal drug toxicity, and advancing the field of regenerative medicine with kidney cells.
Summary
Researchers have developed a chemically defined, serum-free protocol for the prolonged in vitro culture of human fetal kidney-derived organoids (hFKOs). Unlike previous models derived from pluripotent stem cells (PSCs), which often suffered from non-renal cell contamination and degraded within four weeks, these hFKOs are generated from isolated NCAM1+ tissue progenitors. This method yields a “pure” kidney organoid model, free of other cell lineages, that remains stable and continues to mature for over six months. This extended viability enables unprecedented long-term studies of renal development, mirroring the in utero maturation process that occurs up to the 34th week of gestation.
Comprehensive analysis using bulk transcriptomics, single-cell RNA sequencing (scRNA-seq), and immunostaining confirmed that hFKOs faithfully recapitulate human kidney development. The organoids self-organize into polarized renal epithelium, contain diverse renal cell populations, and preserve a pool of epithelial progenitors that drive a continuous tubular differentiation axis. Pseudotime analysis detailed the developmental trajectories of both nephrogenic and ureteric bud lineages within the culture. The model proved robust for functional interrogation, allowing for a detailed investigation of developmental pathways crucial to nephrogenesis.
The study specifically explored the role of Notch signaling, for which hFKOs were highly enriched. Pharmacological inhibition of the Notch pathway resulted in a maturation block, characterized by the accumulation of nephron progenitors and a developmental shift toward distal tubule fates, rather than early proximal tubules. This experiment not only provides a model for specific congenital kidney defects but also led to the identification of a novel cell state expressing prominin-1. This unique cell population evades Notch inhibition to generate both proximal and distal tubules, revealing new insights into renal lineage commitment. The hFKO platform thus provides a high-fidelity system for modeling disease, screening for drug toxicity, and advancing regenerative medicine.
Link to the article: https://www.embopress.org/doi/full/10.1038/s44318-025-00504-2
References Namestnikov, M., Cohen-Zontag, O., Omer, D., Gnatek, Y., Goldberg, S., Vincent, T., Singh, S., Shiber, Y., Rafaeli Yehudai, T., Volkov, H., Folkman Genet, D., Urbach, A., Polak-Charcon, S., Grinberg, I., Pode-Shakked, N., Weisz, B., Vaknin, Z., Freedman, B. S., & Dekel, B. (2025). Human fetal kidney organoids model early human nephrogenesis and Notch-driven cell fate. The EMBO Journal. https://doi.org/10.1038/s44318-025-00504-2
