Role of Extracellular Vesicles in TSC Renal Cystogenesis

Tuberous sclerosis complex (TSC) is caused by mutations in <i>TSC1</i> or <i>TSC2</i> genes and affects multiple organs. TSC proteins control cell growth by regulating the activity of the mechanistic target of rapamycin complex 1. Extracellular vesicles (EVs) are membrane-bound particles produced by cells that mediate cellular communication, function, and growth. Although extensive studies regarding the genetic basis of TSC exist, the exact mechanism contributing to its pathogenesis remains unresolved. It has been proposed that EVs generated by renal cyst epithelia of mice and cells with <i>Tsc</i> gene mutations contain factors that alter the function and proliferation of TSC-sufficient cells. To test this, EVs from the kidneys and kidney explants of wildtype and <i>Tsc1</i>KO mice were isolated and characterized by Western blotting, transmission electron microscopy, dynamic light scattering, and fluorescent nanoparticle tracking. Our results show an enrichment in EV-associated markers and particle sizes of similar ranges. RNA-seq and proteomic analyses identified EV shuttle factors. EV RNA and protein shuttle factors showed significant differences. Furthermore, EVs isolated from <i>Tsc1</i>KO mice inhibited the proliferation of M-1 cells. Understanding the role of EVs in cell proliferation and cystogenesis in TSC may lead to the development of new approaches for the treatment of this disease.