Defects in nephrogenesis result in an expansion of the Foxd1+ stromal progenitor population

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;Wt1c/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;Wt1c/c kidneys) and NPC ablation via diphtheria toxin (i.e., Six2cre;RosaDTAc/+), both phenocopy Six2cre;Wt1c/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. KEY POINTSO_LIMutant mouse models targeting the nephron lineage (i.e., Six2cre;Wt1c/c and Wnt4-null mutants which fail to form early nephron structures) suggest that a block in NPC differentiation results in an abnormal expansion of the Foxd1+ stromal progenitor population. C_LIO_LIMutant kidneys with NPC ablation (i.e., Six2cre;RosaDTAc/+) show maintenance of stromal progenitors independent of signals from adjacent nephron progenitors and ureteric bud. C_LIO_LISingle nuclei RNA-seq identifies three subclusters of the Foxd1+ stromal progenitor population at E15.5, including one cluster of proliferating cells and a distinct Fap+, Igf1+, Gria1+, Gdnf- subcluster which appears expanded in Six2cre;Wt1c/c, Wnt4-null, and Six2cre;RosaDTAc/+ mutant kidneys and conserved in human fetal kidneys. C_LI