Abstract: SA-PO0042
Cxcl11 and Neutrophil Signaling Drive Fgf- and Wnt-Mediated Kidney Regeneration in Adult Zebrafish
Session Information
- Development, Stem Cells, and Regenerative Medicine
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 700 Development, Stem Cells, and Regenerative Medicine
Authors
- Olajuyin, Olaleye, Mount Desert Island Biological Laboratory, Salsbury Cove, Maine, United States
- Schenk, Heiko Joachim, Mount Desert Island Biological Laboratory, Salsbury Cove, Maine, United States
- Sampson, William, Mount Desert Island Biological Laboratory, Salsbury Cove, Maine, United States
- Kamei, Caramai Nanae, Mount Desert Island Biological Laboratory, Salsbury Cove, Maine, United States
- Adekeye, Omodasola, University of Maine System, Bangor, Maine, United States
- Drummond, Iain A., Mount Desert Island Biological Laboratory, Salsbury Cove, Maine, United States
Background
Kidney disease affects over 35 million Americans and represents a major global health burden. The shortage of organ donors, combined with the rising number of patients on the transplant waiting list, has intensified the search for alternative therapies. Zebrafish have a remarkable capacity for kidney regeneration due to the persistence of adult renal stem cells. However, the mechanisms that initiate stem cell activation following injury remain unknown.
Methods
Adult zebrafish were subjected to gentamicin-induced kidney injury followed by RNA sequencing. NF-κB activation was assessed using Tg(NFκB:GFP) reporter fish and pharmacological inhibition. To determine whether inflammation alone could induce regeneration, zebrafish were injected with immune activators, including lipopolysaccharide, Zymosan, and poly IC. Cytokine expression, kim-1 expression, nephron formation, and proliferation were evaluated by gene expression analysis, Lhx1a staining, and EdU incorporation. Candidate cytokines identified by RNA-seq were screened for regenerative activity. Neutrophil function was examined using transgenic zebrafish expressing dominant-negative rac2, and Wnt signaling rescue experiments were performed using CHIR.
Results
RNA sequencing revealed a strong inflammatory response in kidney epithelial cells at two days post-injury, followed by formation of lhx1a+ neo nephrons at seven days post-injury. NF-κB signaling was significantly upregulated after injury, and inhibition of NF-κB impaired nephron regeneration, demonstrating its requirement. Induction of inflammation in the absence of injury was sufficient to stimulate nephron formation and cellular proliferation without increasing Kim-1 expression. Among cytokines identified from RNA-seq, Cxcl11 was sufficient to induce FGF-dependent renal progenitor cell aggregation but insufficient to promote Wnt-dependent epithelial differentiation. In zebrafish with impaired neutrophil function, injury activated FGF signaling but failed to induce wnt9b and downstream Wnt target genes, resulting in arrest at the aggregate stage. Treatment with the Wnt agonist CHIR rescued this regenerative defect.
Conclusion
Our findings demonstrate that an injury-induced, sterile immune response regulates kidney regeneration by establishing a nephrogenic niche of Fgf and Wnt signaling that supports tissue-resident kidney stem cell differentiation into functional nephrons.
Acknowledgment
Image collection was performed with the assistance of the MDI Biological Laboratory Light Microscopy Facility (RRID SCR 019166). Animal husbandry was supported by the MDIBL COBRE Comparative Animal Models Core (P30GM154610).
Funding
- NIDDK Support