Exosomes mediate the acquisition of the disease phenotypes by cells with normal genome in tuberous sclerosis complex

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...

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Bibliographic Details
Published in:Oncogene 2016-06, Vol.35 (23), p.3027-3036
Main Authors: Patel, B, Patel, J, Cho, J-H, Manne, S, Bonala, S, Henske, E, Roegiers, F, Markiewski, M, Karbowniczek, M
Format: Article
Language:English
Subjects:
Angiomyolipoma
Animals
Cancer
Cell activation
Cell differentiation
Cell organelles
Cell Proliferation - physiology
Development and progression
Exosomes
Exosomes - genetics
Exosomes - metabolism
Genetic aspects
Genome
Genomes
Genotype & phenotype
Health aspects
Humans
Mice
Neural stem cells
Neural tube
Notch1 protein
Null cells
Pathogenesis
Phenotype
Phenotypes
Presenilin 1
Progenitor cells
Properties
Rapamycin
Secretase
TOR protein
Tuberous sclerosis
Tuberous Sclerosis - genetics
Tuberous Sclerosis - metabolism
Tuberous Sclerosis - pathology
Tuberous Sclerosis Complex 1
Tuberous Sclerosis Complex 2
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Summary: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2015.358