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2017 ; 8
(ä): 347
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Extracellular Vesicles Mediate Radiation-Induced Systemic Bystander Signals in
the Bone Marrow and Spleen
#MMPMID28396668
Szatmári T
; Kis D
; Bogdándi EN
; Benedek A
; Bright S
; Bowler D
; Persa E
; Kis E
; Balogh A
; Naszályi LN
; Kadhim M
; Sáfrány G
; Lumniczky K
Front Immunol
2017[]; 8
(ä): 347
PMID28396668
show ga
Radiation-induced bystander effects refer to the induction of biological changes
in cells not directly hit by radiation implying that the number of cells affected
by radiation is larger than the actual number of irradiated cells. Recent in
vitro studies suggest the role of extracellular vesicles (EVs) in mediating
radiation-induced bystander signals, but in vivo investigations are still
lacking. Here, we report an in vivo study investigating the role of EVs in
mediating radiation effects. C57BL/6 mice were total-body irradiated with X-rays
(0.1, 0.25, 2?Gy), and 24?h later, EVs were isolated from the bone marrow (BM)
and were intravenously injected into unirradiated (so-called bystander) animals.
EV-induced systemic effects were compared to radiation effects in the directly
irradiated animals. Similar to direct radiation, EVs from irradiated mice induced
complex DNA damage in EV-recipient animals, manifested in an increased level of
chromosomal aberrations and the activation of the DNA damage response. However,
while DNA damage after direct irradiation increased with the dose, EV-induced
effects peaked at lower doses. A significantly reduced hematopoietic stem cell
pool in the BM as well as CD4(+) and CD8(+) lymphocyte pool in the spleen was
detected in mice injected with EVs isolated from animals irradiated with 2?Gy.
These EV-induced alterations were comparable to changes present in the directly
irradiated mice. The pool of TLR4-expressing dendritic cells was different in the
directly irradiated mice, where it increased after 2?Gy and in the EV-recipient
animals, where it strongly decreased in a dose-independent manner. A panel of
eight differentially expressed microRNAs (miRNA) was identified in the EVs
originating from both low- and high-dose-irradiated mice, with a predicted
involvement in pathways related to DNA damage repair, hematopoietic, and immune
system regulation, suggesting a direct involvement of these pathways in mediating
radiation-induced systemic effects. In conclusion, we proved the role of EVs in
transmitting certain radiation effects, identified miRNAs carried by EVs
potentially responsible for these effects, and showed that the pattern of changes
was often different in the directly irradiated and EV-recipient bystander mice,
suggesting different mechanisms.