TY - JOUR
T1 - Human fetal kidney organoids model early human nephrogenesis and Notch-driven cell fate
AU - Namestnikov, Michael
AU - Cohen-Zontag, Osnat
AU - Omer, Dorit
AU - Gnatek, Yehudit
AU - Goldberg, Sanja
AU - Vincent, Thomas
AU - Singh, Swati
AU - Shiber, Yair
AU - Rafaeli Yehudai, Tal
AU - Volkov, Hadas
AU - Folkman Genet, Dani
AU - Urbach, Achia
AU - Polak-Charcon, Sylvie
AU - Grinberg, Igor
AU - Pode-Shakked, Naomi
AU - Weisz, Boaz
AU - Vaknin, Zvi
AU - Freedman, Benjamin S.
AU - Dekel, Benjamin
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/9/1
Y1 - 2025/9/1
N2 - Pluripotent stem cell (PSC)–derived kidney organoids are used to model human renal development and disease; however, accessible models of human fetal development to benchmark PSC-derived organoids remain underdeveloped. Here, we establish a chemically defined, serum-free protocol for prolonged culture of human fetal kidney-derived organoids (hFKOs) in vitro. hFKOs self-organize into polarized renal epithelium, reinitiate from NCAM1+ progenitors, and recapitulate nephrogenic and ureteric bud lineages. Bulk transcriptomics, single-cell RNA sequencing, pseudotime analysis, and immunostaining revealed diverse renal tissue cell populations, with a preserved epithelial progenitor pool and tubular differentiation axis. hFKOs were enriched for Notch signaling genes, enabling single-cell analysis of pharmacological Notch inhibition. This revealed a maturation block with increased nephron progenitors and a shift toward distal over early proximal tubule fates. We also identified a novel prominin-1-expressing cell state that evades Notch inhibition to generate both proximal and distal tubules. Overall, hFKOs provide a faithful model to gain insights into human kidney development, advancing the fields of stem cell biology and regenerative medicine.
AB - Pluripotent stem cell (PSC)–derived kidney organoids are used to model human renal development and disease; however, accessible models of human fetal development to benchmark PSC-derived organoids remain underdeveloped. Here, we establish a chemically defined, serum-free protocol for prolonged culture of human fetal kidney-derived organoids (hFKOs) in vitro. hFKOs self-organize into polarized renal epithelium, reinitiate from NCAM1+ progenitors, and recapitulate nephrogenic and ureteric bud lineages. Bulk transcriptomics, single-cell RNA sequencing, pseudotime analysis, and immunostaining revealed diverse renal tissue cell populations, with a preserved epithelial progenitor pool and tubular differentiation axis. hFKOs were enriched for Notch signaling genes, enabling single-cell analysis of pharmacological Notch inhibition. This revealed a maturation block with increased nephron progenitors and a shift toward distal over early proximal tubule fates. We also identified a novel prominin-1-expressing cell state that evades Notch inhibition to generate both proximal and distal tubules. Overall, hFKOs provide a faithful model to gain insights into human kidney development, advancing the fields of stem cell biology and regenerative medicine.
KW - Human Fetal Kidney
KW - Kidney Organoids
KW - Nephrogenesis
KW - Notch Pathway
KW - Single-cell Transcriptomics
UR - https://www.scopus.com/pages/publications/105011277272
U2 - 10.1038/s44318-025-00504-2
DO - 10.1038/s44318-025-00504-2
M3 - Article
C2 - 40691416
AN - SCOPUS:105011277272
SN - 0261-4189
VL - 44
SP - 4681
EP - 4719
JO - EMBO Journal
JF - EMBO Journal
IS - 17
ER -