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.

TSC 肾囊性疾病知之甚少，也没有批准的治疗方法。在Tsc囊性疾病的新的主要细胞靶向鼠模型中，肾囊性上皮主要由具有完整Tsc2基因的A 型闰细胞组成，尽管这些细胞表现出Tsc- 突变疾病表型。我们在谱系追踪和细胞外囊泡 (EV) 表征实验中使用了新衍生的靶向鼠模型，在 EV 表征和细胞诱导实验中使用了细胞培养模型来了解 TSC 的囊肿形成。使用谱系追踪实验，我们发现主要细胞经历克隆扩增，但对囊肿贡献的细胞很少。我们确定囊性肾脏比非囊性肾脏含有更多的间质 EV，在尿液中排泄更少的 EV，并且在囊液中含有 EV。此外，Tsc2的丢失EV 产生细胞中的基因极大地改变了 EV 对肾小管上皮细胞的影响，从而使上皮细胞的分泌和增殖途径活性增加。我们证明 mTORC1 通路活性独立于 EV 的产生，并且单个细胞系的 EV 效应可能有很大差异。TSC cystogenesis 涉及基因完整细胞的显着贡献，这些细胞被突变细胞衍生的 EV 征召到突变表型。