Abstract: FR-PO0099
Spatial Transcriptomics to Define ADPKD Cyst Morphology and Interrogate Localized Ligand-Receptor Signaling, Anchor Genes, and Enriched Cystic Pathways
Session Information
- ADPKD and Cystic Kidney Disease - 2
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)
Authors
- Robichaud, Jielu Hao, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Afrin, Humayra, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Harris, Peter C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Chebib, Fouad T., Mayo Clinic in Florida, Jacksonville, Florida, United States
- Gupta, Navin R., Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background
ADPKD is the most common inherited cause of kidney failure with PKD1 mutations conferring the greatest severity. Despite our understanding of genotype-phenotype causality and molecular underpinnings, there are few treatments and no cure. Characterization of human disease may help define the faithfulness and utility of disease models, focusing efforts on clinically relevant pathomechanisms to improve translation and drug discovery
Methods
An FFPE block of cystic ADPKD-PKD1 kidney due to a pathogenic PKD1 deletion (c.9668_9694del; p.Thr3223_Glu3231del) was cryosectioned, deparaffinized, H&E stained, and de-crosslinked with probe transfer onto a Visium V4 slide. Probes were extended and amplified for library construction. ADPKD-PKD1 library was sequenced with >170 million 150bp paired-end reads using Illumina NovaSeq 6000. Reads were aligned with space ranger v3.1.2 using the GRCh38 reference genome, normalized with Suerat SingelCellTransform pipeline, and cell ID via seurat anchor-based label transfer. DEG analysis used Seurat FindMarkers(). CellChat v2 applied to identify cell-cell interactions
Results
Cellchat v2 identified ligand-receptor interactions between cysts and/or neighboring stroma to elucidate VEGI (TNFSF15/TNFRSF25), TWEAK (TNFSF12 /TNFRSF12A), MIF (MIF/CD74), osteopontin (SPP1/ [CD44/αVβ3]), and TENASCIN (TNC/ [ITGA9/ V_ITGB1/3/6 or SDC1/4] as potential therapeutic targets. Principal cell (PC) splitting revealed a subcluster enriched in cysts whose top DEGs included GLIS2 and identified NR4A3, HMGCS2, VTCN1, SMIM5, ATP1B3, and MSC, which best served as a cystic anchor gene by RNA expression. Cystic PCs standardized to non-cystic delineated potentials of cystic transformation. Top DEGs included YAP, SMAD3, and the TWEAK receptor. Pathway analysis identified TGF-β, WNT, and integrins, while implicating nicotinic acetylcholine receptor, cadherin, toll receptor, and CCKR signaling.
Conclusion
ST defines gene expression in ADPKD-PKD1, permitting cysts to be defined morphologically and then characterized transcriptionally; with emphasis on localized ligand-receptor signals emanating from and into cysts, interrogating cyst anchor genes, and identifying molecular pathways of cystic transformation, in efforts to dually provide a positive control for disease models and identify putative druggable targets.
Acknowledgment
NIDDK U24DK126110 (PKD-RRC subaward); NIDDK U54DK144863 (Mayo Clinic Polycystic Kidney Disease Research Core Center); NIDDK P30 DK090728 (Mayo Clinic Robert M. and Billie Kelley Pimie Translational PKD Research Center)
Funding
- NIDDK Support