Ablation of the Renal Stroma Defines Its Critical Role in Nephron Progenitor and Vasculature Patterning

Stephanie Hum,Christopher Rymer,Daniel Bushnell,Sunder Sims-Lucas,Caitlin Schaefer,Shree Ram Singh

doi:10.1371/journal.pone.0088400

Stephanie Hum, Christopher Rymer + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0088400

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Abstract

The renal stroma is an embryonic cell population located in the cortex that provides a structural framework as well as a source of endothelial progenitors for the developing kidney. The exact role of the renal stroma in normal kidney development hasn't been clearly defined. However, previous studies have shown that the genetic deletion of Foxd1, a renal stroma specific gene, leads to severe kidney malformations confirming the importance of stroma in normal kidney development. This study further investigates the role of renal stroma by ablating Foxd1-derived stroma cells themselves and observing the response of the remaining cell populations. A Foxd1cre (renal stroma specific) mouse was crossed with a diphtheria toxin mouse (DTA) to specifically induce apoptosis in stromal cells. Histological examination of kidneys at embryonic day 13.5–18.5 showed a lack of stromal tissue, mispatterning of renal structures, and dysplastic and/or fused horseshoe kidneys. Immunofluorescence staining of nephron progenitors, vasculature, ureteric epithelium, differentiated nephron progenitors, and vascular supportive cells revealed that mutants had thickened nephron progenitor caps, cortical regions devoid of nephron progenitors, aberrant vessel patterning and thickening, ureteric branching defects and migration of differentiated nephron structures into the medulla. The similarities between the renal deformities caused by Foxd1 genetic knockout and Foxd1DTA mouse models reveal the importance of Foxd1 in mediating and maintaining the functional integrity of the renal stroma.

Highlights

Development of the mature kidney involves complex interactions between the metanephric mesenchyme and the ureteric epithelium [1,2]
The renal stroma gives rise to the renal capsule, interstitium, mesangium and many of the vascular supportive cells [6]
The ablation model of Foxd1 using diphtheria toxin mouse (DTA) in many ways phenocopied the knockout, suggesting that Foxd1 signaling is likely the critical factor-governing kidney patterning from the renal stroma

Summary

Introduction

Development of the mature kidney involves complex interactions between the metanephric mesenchyme and the ureteric epithelium [1,2]. The renal stroma interdigitates between the nephron progenitor caps and ureteric bud branches forming the primary renal interstitium [5]. The ablation of the Foxd1 cells revealed critical extensions of the previous models including the mispatterning of the differentiated nephron structures and the developing vasculature.

Results

Conclusion