title: Exosomes mediate the acquisition of the disease phenotypes by cells with normal genome in tuberous sclerosis complex.
abstract: Functions of extracellular vesicles including exosomes in the pathogenesis of tuberous sclerosis complex (TSC) have not yet been studied. We report that the extracellular vesicles such as exosomes derived from tuberous sclerosis 1 (Tsc1)-null cells transform phenotypes of neighboring wild-type cells in vivo in such manner that they become functionally similar to Tsc1-null cells. The loss of Tsc1 in the mouse neural tube increases the number of the wild-type neuronal progenitors, which is followed by the precocious and transient acceleration of neuronal differentiation of these cells. The mechanisms regulating these changes involve the exosomal delivery of exosomal shuttle Notch1 and Rheb esRNA and component of γ-secretase complex presenilin 1 from Tsc1-null cells to wild-type cells leading to the activation of Notch and Rheb signaling in the recipient cells. The exosome-mediated mechanisms may also operate in the cells of angiomyolipoma (AML), which develops as a result of mutations in TSC1/TSC2 genes in TSC patients, because we observed the reactivation of mammalian target of rapamycin and Notch pathways, driven by the delivery of Rheb and Notch1 esRNA, in AML cells depleted of Rheb that were treated with the exosomes purified from AML cells with the constitutively high Rheb levels.
authors.affiliation: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center, Abilene, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Patel
authors.affiliation: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center, Abilene, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Patel
authors.affiliation: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center, Abilene, TX, USA.
authors.forename: J-H
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center, Abilene, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Manne
authors.affiliation: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center, Abilene, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bonala
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Henske
authors.affiliation: Fox Chase Cancer Center, Cancer Biology Program, Philadelphia, PA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Roegiers
authors.affiliation: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center, Abilene, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Markiewski
authors.affiliation: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center, Abilene, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Karbowniczek
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D055354:Exosomes / Q000235:genetics* / Q000378:metabolism; D016678:Genome; D006801:Humans; D051379:Mice; D010641:Phenotype; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*