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Published on: October 12, 2017
Defects in nephrogenesis result in an expansion of the Foxd1+ stromal progenitor population
Michael G Michalopulos1, Yan Liu2, Dinesh Ravindra Raju2
1Department of Pediatrics, Division of Pediatric Nephrology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Abstract:
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 regulation of the stromal progenitor population. Here, we demonstrate that disruption of the NPC lineage via loss of Wt1 (i.e., Six2cre;Wt1 c/c ) results in an expansion of Foxd1+ stromal progenitor cells. Analyses of the developing stroma in two additional models, including Wnt4-null mutants (which fail to form nephron structures similar to Six2cre;Wt1 c/c kidneys) and NPC ablation via diphtheria toxin (i.e., Six2cre;RosaDTA c/+ ), both phenocopy Six2cre;Wt1 c/c mutants, thus further confirming that defects in the NPC lineage result in abnormal development of the stromal progenitor population. Furthermore, we identify a subcluster of the Foxd1+ stroma that appears expanded in the three mutant mouse models and conserved in human fetal kidneys. Overall, the findings from this study suggest that loss of differentiating nephron structures may result in possible over proliferation of the stromal progenitor population and/or a block in stromal differentiation and further highlight how crosstalk amongst the progenitor cell lineages coordinates multiple aspects of kidney development.
Insights
Disrupting nephron progenitor cells (NPCs) causes kidney stroma progenitor cells to expand. This highlights reciprocal signaling crucial for kidney development and stromal progenitor regulation.
Area of Science:
- Developmental biology
- Renal physiology
- Cell biology
Background:
- Kidney development involves complex reciprocal signaling between nephron progenitor cells (NPCs) and the surrounding stroma.
- While NPC regulation by stromal signals is known, stromal progenitor regulation remains poorly understood.
Purpose of the Study:
- To investigate the regulatory mechanisms governing stromal progenitor populations during kidney development.
- To determine if defects in the nephron progenitor cell lineage impact stromal progenitor cell development.
Main Methods:
- Utilized genetic mouse models including Six2cre;Wt1 mutants, Wnt4-null mutants, and Six2cre;RosaDTA mutants for NPC ablation.
- Analyzed the developing stroma, specifically focusing on Foxd1+ stromal progenitor cells.
- Compared findings across mutant models and human fetal kidneys.
Main Results:
- Loss of Wt1 in NPCs led to an expansion of Foxd1+ stromal progenitor cells.
- NPC ablation and Wnt4-null mutations also resulted in similar stromal progenitor expansion, confirming the NPC lineage's role.
- Identified an expanded subcluster of Foxd1+ stroma in mutant models, conserved in human fetal kidneys.
Conclusions:
- Defects in the NPC lineage disrupt normal stromal progenitor development, leading to expansion and/or blocked differentiation.
- Reciprocal signaling crosstalk between progenitor lineages is essential for coordinated kidney development.
- Findings suggest a potential link between impaired nephron formation and stromal progenitor overproliferation.
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