Abstract
Defects in Nephrogenesis Result in an Expansion of the Foxd1+ Stromal Progenitor Population: TH-PO0538
Journal of the American Society of Nephrology, Vol.36(10S)
10/2025
DOI: 10.1681/ASN.20250hncnw4a
Abstract
Background:
Reciprocal signaling interactions coordinate multiple aspects of kidney development. While signals from the stroma have been shown to regulate nephron progenitor cell (NPC) differentiation, much less is known about how the stromal progenitor population is regulated. Here we sought to use in-vivo mouse models disrupting the NPC lineage to investigate how defects in nephrogenesis may non-autonomously affect stromal development, with the overall goal of uncovering additional mechanisms of cell-lineage crosstalk in development and disease.
Methods:
Three genetically engineered mouse models were examined, including 1) Six2cre;Wt1c/c mutant kidneys, with Wt1 ablation in the NPCs shown to block NPC differentiation, 2) Wnt4-null mutants, which also fail to undergo NPC differentiation but without targeting the self-renewing NPC population as in the Six2cre;Wt1c/c model, and 3) NPC ablation via diphtheria toxin via Six2cre;RosaDTAc/+. Single nuclei RNA-seq (snRNA-seq) provided additional profiling of the Foxd1+ stromal progenitor cells in murine kidneys, which was further evaluated in human fetal kidneys and Wilms tumor samples.
Results:
In all three mutant models, an expansion of the nephrogenic zone stroma was confirmed by immunoassays and in-situ hybridization, demonstrating that defects in nephrogenesis result in an accumulation of the Foxd1+ stromal progenitor population. Additional analyses of control and mutant murine kidneys identified a distinct subcluster of the Foxd1+ stroma, with snRNA-seq suggesting that this subpopulation is conserved in human fetal kidneys and shows transcriptional similarities to the majority of stroma from human Wilms tumor samples, supporting the hypothesis that embryonal tumor stroma maintains a “progenitor-like” phenotype.
Conclusion:
Overall, this study demonstrates that murine models with defects in NPC differentiation result in an abnormal expansion of stromal progenitor cells, further highlighting roles of cell-lineage crosstalk in normal development and its potential to contribute to developmentally related kidney disease, such as Wilms tumor.
Details
- Title: Subtitle
- Defects in Nephrogenesis Result in an Expansion of the Foxd1+ Stromal Progenitor Population: TH-PO0538
- Creators
- Keri A. DrakeMichael G. MichalopulosYan LiuDinesh RavindrarajuJohn T LafinYanru MaDhruv GaurSadiksha KhadkaChao XingAndrew P. McMahonThomas J. Carroll
- Resource Type
- Abstract
- Publication Details
- Journal of the American Society of Nephrology, Vol.36(10S)
- DOI
- 10.1681/ASN.20250hncnw4a
- ISSN
- 1046-6673
- eISSN
- 1533-3450
- Publisher
- American Society of Nephrology
- Language
- English
- Date published
- 10/2025
- Academic Unit
- Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics
- Record Identifier
- 9985019140902771
Metrics
1 Record Views