Role of Extracellular Vesicles in TSC Renal Cystogenesis

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Abstract
Tuberous sclerosis complex (TSC) is caused by mutations in TSC1 or TSC2 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 Tsc 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 Tsc1KO 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 Tsc1KO 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.
Funding Information
  • United States Veterans Administration Department Merit Review Award (2I01BX001000-10, C-4149, NHLBIT32HL007736, NCI P30CA118100)
  • Dialysis Clinics (2I01BX001000-10, C-4149, NHLBIT32HL007736, NCI P30CA118100)
  • National Institutes of Health (2I01BX001000-10, C-4149, NHLBIT32HL007736, NCI P30CA118100)
  • University of New Mexico (UNM) Comprehensive Cancer Center Support (2I01BX001000-10, C-4149, NHLBIT32HL007736, NCI P30CA118100)

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