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Journal ArticleDOI

Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells

07 May 2007-Nature Cell Biology (Nature Publishing Group)-Vol. 9, Iss: 6, pp 654-659
TL;DR: It is shown that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location, and it is proposed that this RNA is called “exosomal shuttle RNA” (esRNA).
Abstract: Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Microarray assessments revealed the presence of mRNA from approximately 1300 genes, many of which are not present in the cytoplasm of the donor cell. In vitro translation proved that the exosome mRNAs were functional. Quality control RNA analysis of total RNA derived from exosomes also revealed presence of small RNAs, including microRNAs. The RNA from mast cell exosomes is transferable to other mouse and human mast cells. After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient cells, indicating that transferred exosomal mRNA can be translated after entering another cell. In summary, we show that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location. We propose that this RNA is called "exosomal shuttle RNA" (esRNA).

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Journal ArticleDOI
TL;DR: It is shown here that miRNAs are present in human plasma in a remarkably stable form that is protected from endogenous RNase activity and established the measurement of tumor-derived mi RNAs in serum or plasma as an important approach for the blood-based detection of human cancer.
Abstract: Improved approaches for the detection of common epithelial malignancies are urgently needed to reduce the worldwide morbidity and mortality caused by cancer. MicroRNAs (miRNAs) are small (≈22 nt) regulatory RNAs that are frequently dysregulated in cancer and have shown promise as tissue-based markers for cancer classification and prognostication. We show here that miRNAs are present in human plasma in a remarkably stable form that is protected from endogenous RNase activity. miRNAs originating from human prostate cancer xenografts enter the circulation, are readily measured in plasma, and can robustly distinguish xenografted mice from controls. This concept extends to cancer in humans, where serum levels of miR-141 (a miRNA expressed in prostate cancer) can distinguish patients with prostate cancer from healthy controls. Our results establish the measurement of tumor-derived miRNAs in serum or plasma as an important approach for the blood-based detection of human cancer.

7,296 citations


Cites background from "Exosome-mediated transfer of mRNAs ..."

  • ...Exosomes are 50- to 90-nm (24), membrane-bound particles that have been reported to be abundant in plasma (25) and that have recently been shown (in cell culture studies) to contain miRNAs (26)....

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Journal ArticleDOI
TL;DR: This review focuses on the characterization of EVs and on currently proposed mechanisms for their formation, targeting, and function.
Abstract: Cells release into the extracellular environment diverse types of membrane vesicles of endosomal and plasma membrane origin called exosomes and microvesicles, respectively. These extracellular vesicles (EVs) represent an important mode of intercellular communication by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and RNA. Deficiencies in our knowledge of the molecular mechanisms for EV formation and lack of methods to interfere with the packaging of cargo or with vesicle release, however, still hamper identification of their physiological relevance in vivo. In this review, we focus on the characterization of EVs and on currently proposed mechanisms for their formation, targeting, and function.

6,141 citations


Cites background from "Exosome-mediated transfer of mRNAs ..."

  • ...A major breakthrough was the demonstration that the cargo of EVs included both mRNA and miRNA and that EVassociated mRNAs could be translated into proteins by target cells (Ratajczak et al., 2006; Valadi et al., 2007)....

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  • ...Many RNAs that were isolated with EVs were found to be enriched relative to the RNA profiles of the originating cells (Ratajczak et al., 2006; Valadi et al., 2007; Skog et al., 2008; Nolte-’t Hoen et al., 2012a), indicating that RNA molecules are selectively incorporated into EVs....

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Journal ArticleDOI
TL;DR: This Review summarizes the current understanding of the mechanistic aspects of microRNA-induced repression of translation and discusses some of the controversies regarding different modes of micro RNA function.
Abstract: MicroRNAs constitute a large family of small, approximately 21-nucleotide-long, non-coding RNAs that have emerged as key post-transcriptional regulators of gene expression in metazoans and plants. In mammals, microRNAs are predicted to control the activity of approximately 30% of all protein-coding genes, and have been shown to participate in the regulation of almost every cellular process investigated so far. By base pairing to mRNAs, microRNAs mediate translational repression or mRNA degradation. This Review summarizes the current understanding of the mechanistic aspects of microRNA-induced repression of translation and discusses some of the controversies regarding different modes of microRNA function.

4,973 citations

Journal ArticleDOI
TL;DR: Extracellular vesicles are now considered as an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids and genetic material.
Abstract: Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising exosomes and microvesicles, which originate from the endosomal system or which are shed from the plasma membrane, respectively They are present in biological fluids and are involved in multiple physiological and pathological processes Extracellular vesicles are now considered as an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids and genetic material Knowledge of the cellular processes that govern extracellular vesicle biology is essential to shed light on the physiological and pathological functions of these vesicles as well as on clinical applications involving their use and/or analysis However, in this expanding field, much remains unknown regarding the origin, biogenesis, secretion, targeting and fate of these vesicles

4,241 citations

Journal ArticleDOI
TL;DR: Tumour-derived microvesicles may provide diagnostic information and aid in therapeutic decisions for cancer patients through a blood test by incorporating an mRNA for a reporter protein into them, and it is demonstrated that messages delivered by microvesicle are translated by recipient cells.
Abstract: Glioblastoma tumour cells release microvesicles (exosomes) containing mRNA, miRNA and angiogenic proteins. These microvesicles are taken up by normal host cells, such as brain microvascular endothelial cells. By incorporating an mRNA for a reporter protein into these microvesicles, we demonstrate that messages delivered by microvesicles are translated by recipient cells. These microvesicles are also enriched in angiogenic proteins and stimulate tubule formation by endothelial cells. Tumour-derived microvesicles therefore serve as a means of delivering genetic information and proteins to recipient cells in the tumour environment. Glioblastoma microvesicles also stimulated proliferation of a human glioma cell line, indicating a self-promoting aspect. Messenger RNA mutant/variants and miRNAs characteristic of gliomas could be detected in serum microvesicles of glioblastoma patients. The tumour-specific EGFRvIII was detected in serum microvesicles from 7 out of 25 glioblastoma patients. Thus, tumour-derived microvesicles may provide diagnostic information and aid in therapeutic decisions for cancer patients through a blood test.

4,118 citations


Cites background from "Exosome-mediated transfer of mRNAs ..."

  • ...It has been shown that microvesicles can transfer some of their contents to other cell type...

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References
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Journal ArticleDOI
TL;DR: The tolerosome is a large vesicular structure that carries MHC class II (MHC II) with bound antigenic peptides sampled from the gut lumen that represents a structure by which fed antigens can be efficiently presented to the immune system.
Abstract: The development of immunological tolerance to orally fed antigens depends on the sampling, processing and transportation events followed in the intestinal epithelium. We present here a description of a "tolerosome": a supra-molecular, exosome-like structure assembled in and released from the small intestinal epithelial cell. The tolerosome is a approximately 40 nm large vesicular structure that carries MHC class II (MHC II) with bound antigenic peptides sampled from the gut lumen. Tolerosomes isolated from serum shortly after antigen feeding or from an in vitro pulsed intestinal epithelial cell line are fully capable of inducing antigen specific tolerance in naive recipient animals. Purified tolerosomes represent a structure by which fed antigens can be efficiently presented to the immune system. Removal of the tolerosomes from serum by ultracentrifugation or absorption of MHC II results in abrogated tolerance development.

302 citations

Journal ArticleDOI
TL;DR: B cell‐derived exosomes express functional integrins, which are capable of mediating anchorage to ECM and cell‐surface adhesion molecules, and may be a novel mode of delivering adhesion signals at distances beyond that of direct cell‐cell contact during inflammation.
Abstract: Exosomes are nanometer-sized vesicles secreted by various cells, with potentially diverse roles in physiology. Although emphasis has been placed on their involvement in immune modulation, their potential for more wide-ranging biological effects has not been appreciated. A common exosome feature is the expression of adhesion molecules, which include the integrin family. We have for the first time addressed the possible function of B cell-derived exosome-integrins by examining adhesive interactions of exosomes (immobilized onto beads) with extracellular matrix (ECM) components and cytokine-treated fibroblasts. Integrin (beta1 and beta2) expression was demonstrated by Western blotting and flow cytometry. Binding studies (with blocking antibodies) demonstrated their function in adhesion to collagen-I, fibronectin, and tumor necrosis factor (TNF)-alpha-activated fibroblasts. Exosome adhesion to TNF-alpha-activated fibroblasts also triggered integrin-dependent changes in cytosolic calcium, measured by single cell imaging. Thus, B cell-derived exosomes express functional integrins, which are capable of mediating anchorage to ECM and cell-surface adhesion molecules, and may be a novel mode of delivering adhesion signals at distances beyond that of direct cell-cell contact during inflammation.

295 citations


"Exosome-mediated transfer of mRNAs ..." refers background in this paper

  • ...Alternatively, exosomes could putatively attach or fuse with the target-cell membrane, delivering exosomal surface proteins and perhaps cytoplasm to the recipient cel...

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Journal ArticleDOI
TL;DR: A detailed characterization of the expression of a panel of markers for various types of immature and mature haematopoietic cells in the HMC‐1 is reported on.
Abstract: The cell line HMC-1, derived from a patient with mast cell leukaemia, is the only established cell line exhibiting a phenotype similar to that of human mast cells. This paper reports on a detailed characterization of the expression of a panel of markers for various types of immature and mature haematopoietic cells in the HMC-1. We also studied the potential of HMC-1 to differentiate upon treatment with conditioned media from the human T-cell line Mo, retinoic acid or DMSO. HMC-1 was found to express several mast cell-related markers. A high expression of Kit, the receptor for stem-cell factor, was detected. The majority of the cells were stained with a MoAb against the mast cell-specific serine protease tryptase. Of particular interest was the finding that beta-tryptase mRNA, but not alpha-tryptase mRNA, was expressed in HMC-1. Using enzyme-histochemistry we were able to show that the beta-tryptase was enzymatically active, indicating that tryptase can form active homotetramers. Both heparin and chondroitin sulfate were found to be present in approximately equal amounts. HMC-1 lacked surface expression of the high-affinity IgE receptor, which was confirmed by the absence of mRNA of the alpha- and beta-chains of the IgE-receptor complex. However, a strong expression of the gamma-chain of the IgE-receptor complex was detected. A positive staining of the monocyte/macrophage marker CD68 was obtained, as well as a strong hybridization signal for the eosinophilic/basophilic-related differentiation marker the Charcot-Leyden crystal. Treatment of HMC-1 with conditioned media from the human T-cell line Mo, retinoic acid or DMSO induced only moderate changes in the surface or intracellular expression of the studied markers. The agents tested neither induced any of the monocyte/granulocyte markers examined, nor expression of the Fc epsilon RI alpha-chain.

264 citations


"Exosome-mediated transfer of mRNAs ..." refers methods in this paper

  • ...MC/9 cells (ATCC, Manassas, VA), the human mast cell line HMC-1 (J, Butterfield, Mayo Clinic, /rochester, MN) and bone marrow mast cells (BMMC) were prepared and cultured as described by ATC...

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Journal Article

259 citations


"Exosome-mediated transfer of mRNAs ..." refers background in this paper

  • ...Two of the best studied miRNAs are lin-4 and let-7 , which are involved in early ( lin-4 ) and late ( let-7 ) developmental timin...

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Journal ArticleDOI
31 Mar 1997-Virology
TL;DR: Electron microscopic analysis of microvesicles revealed that they consisted of particles of various sizes and morphologies, and although HIV-1 particles are known to contain some cellular proteins, microvesicle from HIV-2 infected H9 cells appeared to contain little or no HIV- 1 gp120SU.

225 citations


"Exosome-mediated transfer of mRNAs ..." refers background in this paper

  • ...Recently, several groups have shown that circular membrane fragments called microvesicles also may be involved in cell–cell communication, and may contain mRN...

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