# Epithelial Dynamics of Cystogenesis in Genetic Models of Autosomal Dominant Polycystic Kidney Disease

## TL;DR

This study explores how kidney cysts grow in a genetic kidney disease by tracking cell behavior and developing a mathematical model.

## Contribution

The study identifies epithelial clonal expansion and cell shape changes as key drivers of cyst growth in ADPKD.

## Key findings

- Polycystin-deficient epithelial cells initiate and sustain clonal expansion during cyst progression.
- Cyst-lining cells transition from columnar to flattened morphology, promoting luminal enlargement.
- A mathematical model shows that clonal expansion and cell shape changes together explain exponential cyst growth.

## Abstract

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 or PKD2, is characterized by progressive and exponential enlargement of renal and hepatic cysts. However, the epithelial dynamics that generate this growth pattern remain incompletely understood. Using Brainbow/Confetti multicolor clonal lineage tracing in developmental and adult-onset ADPKD mouse models, we show that polycystin-deficient epithelial cells initiate clonal expansion at early stages of tubule dilation and continue to expand throughout cyst progression. Concurrently, cyst-lining cells undergo a progressive transition from columnar to flattened morphology, which amplifies luminal enlargement independent of cell number. Integrating these measures, we developed a mathematical model demonstrating that the combination of this clonal expansion and epithelial cell shape remodeling is sufficient to produce the exponential growth trajectory observed in ADPKD. Together, these findings define the core epithelial mechanisms that drive cyst initiation and expansion, and may provide a mathematical framework for the emergent exponential growth of cysts.