TSC renal cystic disease is poorly understood and has no approved treatment. In a new principal cell-targeted murine model of

Tsc

cystic disease

the renal cystic epithelium is mostly composed of type A intercalated cells with an intact

Tsc2

gene confirmed by sequencing

although these cells exhibit a

Tsc

-mutant disease phenotype. We used a newly derived targeted murine model in lineage tracing and extracellular vesicle (EV) characterization experiments and a cell culture model in EV characterization and cellular induction experiments to understand TSC cystogenesis. Using lineage tracing experiments

we found principal cells undergo clonal expansion but contribute very few cells to the cyst. We determined that cystic kidneys contain more interstitial EVs than noncystic kidneys

excrete fewer EVs in urine

and contain EVs in cyst fluid. Moreover

the loss of

Tsc2

gene in EV-producing cells greatly changes the effect of EVs on renal tubular epithelium

such that the epithelium develops increased secretory and proliferative pathway activity. We demonstate that the mTORC1 pathway activity is independent form the EV production

and that the EV effects for a single cell line can vary significantly. TSC cystogenesis involves significant contribution from genetically intact cells conscripted to the mutant phenotype by mutant cell derived EVs.