Biology Reference
In-Depth Information
potential of exosomes per se as drug delivery vehicles and in the design of novel
“exosome-inspired” drug delivery vehicles. In this context, the most relevant feature
of exosomes as aforementioned is that they are natural carriers of coding and non-
coding RNA including miRNA between cells. Indeed, in 2006, Baj-Krzyworzeka
et al. described the presence of tumor cell markers and mRNAs in tumor-derived
microvesicles and demonstrated their transfer in vitro into monocytes [
71
] .
Subsequently, in 2007, Valadi et al. discovered the presence of mRNA and miRNA
inside exosomes derived from mast cells and suggested that the ability of exosomes
to deliver nucleic acids to cells at a distance made them ideal candidates as RNA
delivery vehicles [
32
]. At present, over 1,600 mRNAs and more than 700 miRNAs
identified predominantly by microarrays have been reported in 134 studies. The
profile of mRNAs observed in exosomes does not necessarily match the composi-
tion of the donor cells, suggesting that there is a selective loading of specific mRNA
and miRNA molecules into exosomes [
72
]. Most importantly, it has been shown
that exosome-delivered RNAs mediate de novo transcriptional and translational
changes in the recipient cells, suggesting that exosomes are able to deliver their
RNA cargo to the subcellular compartment appropriate for function [
32,
73
] . A
study of the transfer of miRNA from activated T cells to APCs suggested the exis-
tence of immune synapse-mediated exosomal transport, providing evidence for the
directed and unidirectional transfer of miRNA-carrying exosomes through the
immune synapse between the donor T cells and the recipient APCs [
74
] . DC-derived
exosomes were also shown to transport miRNA to recipient DCs and to conse-
quently influence the regulation of the miRNA targets in recipient DCs [
75
] .
Fluorescently labeled glioblastoma microvesicles have been shown to transfer
Gaussia luciferase (Gluc) mRNA to human brain microvascular endothelial cells
(HBMVECs), leading to expression of the Gluc protein in the recipient cells, dem-
onstrating de novo translation of the transferred Gluc mRNA in the recipients [
76
] .
In another study, incubation of human mast cells with exosomes derived from
mouse cells resulted in the expression of the donor mouse proteins in the recipient
human cells [
32
]. It was also shown that exosomes from cultured monocytes con-
tained components of RNA-induced silencing complex (RISC), such as AGO2 and
its interacting partner GW182 [
77
]. Importantly, mature miRNAs and their target
mRNAs also co-localize to MVBs, but not to exosomes, raising the possibility that
miRNA-loaded RISC assembly takes place in MVBs, and that exosomes are intrin-
sically implicated in miRNA-induced silencing, and more intriguingly, that silenc-
ing by miRNA may occur in trans in cells that do not express the miRNA (Fig.
9.3
).
The ability of exosomes to transfer RNA and miRNA between cells and to subse-
quently mediate changes in gene regulation in the recipient cells has now been dem-
onstrated with a variety of donor and recipient cell types. This, together with their
implication in the RISC-induced silencing, highlights their potential as RNAi deliv-
ery vehicles and raises the further opportunity for the design of “exosome-inspired”
delivery vehicles.
Search WWH ::
Custom Search