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Kidney Week

Abstract: PO0611

ZEB2 Is Essential for FOXD1+ Kidney Stromal Progenitor Cell Differentiation During Kidney Development

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • Kumar, Sudhir, Boston University School of Medicine, Boston, Massachusetts, United States
  • Fan, Xueping, Boston University School of Medicine, Boston, Massachusetts, United States
  • Milo Rasouly, Hila, Boston University School of Medicine, Boston, Massachusetts, United States
  • Sharma, Richa, Boston University School of Medicine, Boston, Massachusetts, United States
  • Salant, David J., Boston University School of Medicine, Boston, Massachusetts, United States
  • Lu, Weining, Boston University School of Medicine, Boston, Massachusetts, United States
Background

FOXD1+ derived stromal cells are essential for normal kidney development. They give rise to pericytes and resident fibroblasts that support the kidney vasculature and also cooperate with cells that give rise to the developing nephron. However, FOXD1+ derived stromal progenitors may also serve as precursors of myofibroblasts in kidney fibrosis. The signals that regulate the differentiation of FOXD1+ stromal progenitors are not well understood. Given that zinc finger E-box-binding homeobox2 (ZEB2), a SMAD-interacting transcription factor, is expressed in developing kidney stromal cells, we examined the role of ZEB2 in kidney stromal cell differentiation in the developing mouse kidney.

Methods

We generated Zeb2 stromal-specific conditional knockout mice (cKO) by crossing Zeb2 flox mice with Foxd1Cre mice and analyzed the phenotype of homozygous Zeb2flox/flox;Foxd1Cre+ mice (Zeb2 cKO) and their wild-type littermate controls. Kidney histology, renal function, and lifespan were studied in Zeb2 cKO mice. Cell fate mapping was performed using tdTomato mice. Protein expression analyses were performed by immunostaining and Western blotting of several markers for stromal progenitors, collagen, pericytes, fibroblasts, myofibroblasts, endothelial cells, renal tubules, and SMAD proteins in Zeb2 cKO and wild-type controls. Nephrogenesis was analyzed by immunostaining using nephron morphogenesis markers SIX2, WT1, nephrin, and Jagged1.

Results

Deletion of mouse Zeb2 in FOXD1+ stromal progenitors produced dysplastic and hypovascular kidneys. The Zeb2 deficient FOXD1+ stromal progenitors in these kidneys took on a myofibroblast cell fate that led to kidney fibrosis and kidney failure. Cell marker studies confirmed that these myofibroblasts expressed pericyte and resident fibroblast markers including PDGFRβ, CSPG4, Desmin, GLI1, and NT5E. Notably, increased interstitial collagen deposition associated with loss of Zeb2 in FOXD1+ stromal progenitors was accompanied by increased expression of activated SMAD1/5/8, SMAD2/3, and SMAD4.

Conclusion

Our study identifies a key role of ZEB2 in maintaining the cell fate of FOXD1+ stromal progenitors during kidney development and loss of ZEB2 leads to differentiation of FOXD1+ stromal progenitors into myofibroblasts and kidney fibrosis.

Funding

  • NIDDK Support