Abstract: SA-PO0004
Generation of Human Collecting Duct Organoids with Spatial Patterning and Functional Principal and Intercalated Cells
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
- Schreiber, Megan, University of Southern California, Los Angeles, California, United States
- Zhang, Chennan, University of Southern California, Los Angeles, California, United States
- Xu, Cong, University of Southern California, Los Angeles, California, United States
- Li, Zhongwei, University of Southern California, Los Angeles, California, United States
Background
The kidney maintains systemic homeostasis through blood filtration, electrolyte balance, and the excretion of metabolic waste. Within nephrons, a specialized tubule mediated system filters the blood and reabsorbs essential nutrients, to create primitive urine. Multiple nephrons drain into a single collecting duct (CD) for final filtration, making the CD vital for maintaining healthy blood pressure and pH levels. The CD is made up of two major cell populations the principal cells (PC) and intercalated cells (IC). PCs mediate water and sodium reabsorption, while ICs maintain PH balance. Dysfunction in these cell types can cause a multitude of issues in fluid, electrolyte, or pH homeostasis that ultimately can lead to disease. Notably autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disorder, primarily affects the CD and principal cells are the predominant site of cyst formation.
Methods
Despite its clinical significance, existing models fail to recapitulate the late-stage human CD maturation in development. Bulk RNA-seq was used to identify key developmental regulating cell-fate specification during the UB to CD transition in our human pluripotent stem cell (hPSC) derived organoids. To validate these findings, we generated a dual reporter line for AQP2-GFP (PC)/FOXI1-mCherry (IC) to track in real-time increases of these important markers with the introduction of specific small molecules to drive further maturation of the CD organoids. CRISPR/Cas9 genome editing was used to establish an efficient, scalable organoid model for ADPKD.
Results
These CD organoids recapitulate human CD development, transitioning sequentially from UB tip, UB trunk, to a mature spatially patterned CD. This model features elongated tubules and expression of functional PCs and ICs, validated by PC-associated ion channel activity and IC-associated acid-base transport activity. Additionally, the CD organoids were used to model ADPKD and captured key phenotypic and pathogenic features observed in ADPKD patients.
Conclusion
Our spatially patterned CD organoids establish a robust model for investigating human-specific kidney development focused on the UB lineage. The development of a scaled-up CD ADPKD model faithfully recapitulates the disease state and can be used to further understand pathogenesis and identify therapeutics.