Abstract: TH-PO389
Bridging the Gap of Late-Gestation Human Nephrogenesis Using a Nonhuman Primate Model
Session Information
- Development, Organoids, Injury, and Regeneration
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 600 Development, Stem Cells, and Regenerative Medicine
Authors
- Thakkar, Kairavee, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- Yarlagadda, Sunitha, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- Alkhudairy, Lyan, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- Potter, Andrew, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- Thorner, Konrad, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- Salomonis, Nathan, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- Kopan, Raphael, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- Schuh, Meredith Posner, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
Background
Prematurity is associated with low nephron endowment and an increased risk of chronic kidney disease. Human nephrogenesis is complete at 34-36 weeks gestation, with 60% of nephrons forming during 3rd trimester through lateral branch nephrogenesis (LBN). To overcome the barriers of studying late-gestation human tissue, we utilized a non-human primate model (rhesus macaque) to study LBN.
Methods
Single-cell RNA-sequencing (scRNA-Seq) was performed on 9 cortically-enriched fetal rhesus kidneys from late second trimester and third trimester during LBN. This data was integrated with publicly available human scRNA-seq datasets from 8-18 weeks gestation kidneys (n=8) using state-of-the-art bioinformatics pipelines. Ligand-receptor interactions were assessed and validated on human and rhesus archival tissue using RNAScope.
Results
scRNA-Seq of 64,782 rhesus cells revealed 37 transcriptionally distinct cell populations, including four nephron progenitor cell (NPC) clusters (7937 cells) (Figure 1). We noted increased SFRP1, FZD4, FZD6, and TLE2 and decreased FZD7, SHISA2, SHISA3, and TLE4 within the rhesus late-gestation NPC compared to mid-gestation human NPC, supporting a compositional shift in WNT signaling within the naive NPC population during LBN. We identified changes in constitution of the FGF and Semaphorin (SEMA3) pathways as well.
Conclusion
The rhesus macaque uniquely enables molecular studies of late gestation primate nephrogenesis. Our study supports the hypothesis that a compositional shift in key pathways within the naive NPC population during LBN may underly the switch from branch phase nephrogenesis to lateral branching. Future studies will focus on maintaining this signaling environment to promote nephron formation in preterm infants.
Funding
- NIDDK Support