Abstract: FR-PO367
Consequences of Centrosome Dysfunction in Stromal Progenitors During Kidney Development and Repair
Session Information
- Genetics, Development, Regeneration
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Development‚ Stem Cells‚ and Regenerative Medicine
- 500 Development‚ Stem Cells‚ and Regenerative Medicine
Authors
- Langner, Ewa, Washington University in St Louis, St Louis, Missouri, United States
- Cheng, Tao, Washington University in St Louis, St Louis, Missouri, United States
- Kefalogianni, Eirini, Washington University in St Louis, St Louis, Missouri, United States
- Wang, Baolin, Cornell University, Ithaca, New York, United States
- Mahjoub, Moe, Washington University in St Louis, St Louis, Missouri, United States
Background
Reciprocal signaling between progenitor cells of the cap mesenchyme, ureteric bud epithelium and stromal mesenchyme (SM) is critical for mammalian kidney morphogenesis. Several signaling pathways involved in the growth and differentiation of these progenitors are regulated by the centrosome, the main microtubule-organizing center, and its associated structure the cilium. Mutations in genes that disrupt centrosome biogenesis or function cause congenital renal dysplasia and cystic-fibrotic pathologies. However, it is unknown how defects in centrosome biogenesis impact renal interstitial progenitor cells. Here, we examined the consequences of defective centrosome biogenesis on SM progenitor cell growth, fate determination, formation of SM-derived lineages, and overall kidney development in mice.
Methods
Deletion of Cep120, the ciliopathy gene essential for centrosome duplication, was induced in the SM by crossing Cep120F/F mice with the FoxD1-Cre strain. Changes in kidney morphology and function upon centrosome loss were assessed at embryonic and postnatal time points and following unilateral ureteral obstruction (UUO) injury.
Results
Ablation of Cep120 blocked centrosome biogenesis in FoxD1-derived cells and led to reduced abundance of pericytes, peritubular fibroblasts and mesangial cells at birth. This was caused by delayed mitosis, abnormal Wnt and Hedgehog signaling leading to reduced proliferation. There was a concomitant delay in maturation of nephron tubular structures resulting in small, dysplastic kidneys by P15. Mutants differed in phenotypic severity, with survival rates between 1-5 months of age. Remarkably, mutants showed no change in kidney function nor developed spontaneous fibrosis. In contrast, loss of centrosomes caused increased proliferation of pericytes and fibroblasts following UUO injury, and led to elevated levels of profibrotic signaling factors.
Conclusion
Our results indicate that centrosome loss in the SM disrupts kidney morphology but not function during embryonic development. In contrast, centrosome loss sensitizes the kidneys leading to accelerated fibrosis following injury. These data highlight the contribution of defective centrosome biogenesis in the developing renal interstitium, and identify possible pathways as targets for therapy.
Funding
- NIDDK Support