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<p>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<sup>+</sup> 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&#xa0;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.</p>

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Human fetal kidney organoids model early human nephrogenesis and Notch-driven cell fate

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月21日

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  • Michael Namestnikov,
  • Osnat Cohen-Zontag,
  • Dorit Omer,
  • Yehudit Gnatek,
  • Sanja Goldberg,
  • Thomas Vincent,
  • Swati Singh,
  • Yair Shiber,
  • Tal Rafaeli Yehudai,
  • Hadas Volkov,
  • Dani Folkman Genet,
  • Achia Urbach,
  • Sylvie Polak-Charcon,
  • Igor Grinberg,
  • Naomi Pode-Shakked,
  • Boaz Weisz,
  • Zvi Vaknin,
  • Benjamin S Freedman,
  • Benjamin Dekel

摘要

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.