Nanotubes, exosomes, and nucleic acid–binding peptides provide novel mechanisms of intercellular communication in eukaryotic cells: implications in health and disease

Belting, Mattias; Wittrup, Anders

doi:10.1083/jcb.200810038

Cited by 152 publications

(124 citation statements)

References 32 publications

(40 reference statements)

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“…Previous studies showed the presence of cellular miRNAs in vesicles isolated from human peripheral blood (5-7). Taken together these data are consistent with the notion of functional miRNA transfer through exosomes as a possible mechanism of intercellular communication and immune regulation (34), although alternative methods of transfer cannot be ruled out (8,35).…”

Section: Discussionsupporting

confidence: 77%

“…Curiously, miRNAs are not strictly cellular but are secreted through the release of small vesicles called "exosomes" and therefore present extracellularly in the peripheral blood and in cell-culture media (5)(6)(7). It has been suggested that exosomeassociated miRNAs have a role in intercellular communication, although concrete evidence for this has been lacking (6)(7)(8)(9). For example, the dynamics of miRNA secretion through exosomes and the proposed transfer mechanisms remain poorly understood.…”

mentioning

confidence: 99%

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Functional delivery of viral miRNAs via exosomes

Pegtel

Cosmopoulos

Thorley‐Lawson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

1,440

1,227

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Noncoding regulatory microRNAs (miRNAs) of cellular and viral origin control gene expression by repressing the translation of mRNAs into protein. Interestingly, miRNAs are secreted actively through small vesicles called "exosomes" that protect them from degradation by RNases, suggesting that these miRNAs may function outside the cell in which they were produced. Here we demonstrate that miRNAs secreted by EBV-infected cells are transferred to and act in uninfected recipient cells. Using a quantitative RT-PCR approach, we demonstrate that mature EBV-encoded miRNAs are secreted by EBV-infected B cells through exosomes. These EBV-miRNAs are functional because internalization of exosomes by MoDC results in a dose-dependent, miRNAmediated repression of confirmed EBV target genes, including CXCL11/ ITAC, an immunoregulatory gene down-regulated in primary EBVassociated lymphomas. We demonstrate that throughout coculture of EBV-infected B cells EBV-miRNAs accumulate in noninfected neighboring MoDC and show that this accumulation is mediated by transfer of exosomes. Thus, the exogenous EBV-miRNAs transferred through exosomes are delivered to subcellular sites of gene repression in recipient cells. Finally, we show in peripheral blood mononuclear cells from patients with increased EBV load that, although EBV DNA is restricted to the circulating B-cell population, EBV BART miRNAs are present in both B-cell and non-B-cell fractions, suggestive of miRNA transfer. Taken together our findings are consistent with miRNA-mediated gene silencing as a potential mechanism of intercellular communication between cells of the immune system that may be exploited by the persistent human γ-herpesvirus EBV.

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Section: Discussionsupporting

confidence: 77%

mentioning

confidence: 99%

Functional delivery of viral miRNAs via exosomes

Pegtel

Cosmopoulos

Thorley‐Lawson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

1,440

1,227

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“…We detected some variability within the mobilized miR126 -/-mice, consistent with the variability of other defective phenotypes in these mice. 35 Thus, these results indicate that miR126-null mice are defective at mobilizing HSPC after G-CSF treatment.…”

Section: Exo From Controlmentioning

confidence: 69%

“…Previous studies showed that miR126-null mice have a distinctive vascular phenotype with leaky vessels and hemorrhages; approximately 40-50% of mice die in utero or perinatally. 35,36 We mobilized with G-CSF groups of 13-week old miR126 +/+ and miR126 -/-littermates and compared them to non-mobilized mice.…”

Section: Exo From Controlmentioning

confidence: 99%

MicroRNA126 contributes to granulocyte colony-stimulating factor-induced hematopoietic progenitor cell mobilization by reducing the expression of vascular cell adhesion molecule 1

Salvucci

Jiang²,

Gasperini³

et al. 2012

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundMobilization of hematopoietic stem/progenitor cells from the bone marrow to the peripheral blood by granulocyte colony-stimulating factor is the primary means to acquire stem cell grafts for hematopoietic cell transplantation. Since hematopoietic stem/progenitor cells represent a minority of all blood cells mobilized by granulocyte colony-stimulating factor, the underlying mechanisms need to be understood in order to develop selective drugs. Design and MethodsWe analyzed phenotypic, biochemical and genetic changes in bone marrow cell populations from granulocyte colony-stimulating factor-mobilized and control mice, and linked such changes to effective mobilization of hematopoietic stem/progenitor cells. ResultsWe show that granulocyte colony-stimulating factor indirectly reduces expression of surface vascular cell adhesion molecule 1 on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells by promoting the accumulation of microRNA-126 (miR126)-containing microvescicles in the bone marrow extracellular compartment. We found that hematopoietic stem/progenitor cells, stromal cells and endothelial cells readily incorporate these miR126-loaded microvescicles, and that miR126 represses vascular cell adhesion molecule 1 expression on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells. In line with this, miR126-null mice displayed a reduced mobilization response to granulocyte colony-stimulating factor. ConclusionsOur results implicate miR126 in the regulation of hematopoietic stem/progenitor cell trafficking between the bone marrow and peripheral sites, clarify the role of vascular cell adhesion molecule 1 in granulocyte colony-stimulating factor-mediated mobilization, and have important implications for improved approaches to selective mobilization of hematopoietic stem/progenitor cells.

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“…Extensive studies on tumor cell-derived exosomes and their roles in intercellular communication in the tumor microenvironment have been performed (6,8,9,(20)(21)(22)(23)(24). The tumor cell-derived exosome is known to manipulate the surrounding microenvironment to promote angiogenesis, invasion and metastasis, as well as escape immune surveillance (10).…”

Section: Discussionmentioning

confidence: 99%

The 786-0 renal cancer cell-derived exosomes promote angiogenesis by downregulating the expression of hepatocyte cell adhesion molecule

Zhang

Luo

et al. 2013

Molecular Medicine Reports

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Abstract.The aims of the current study were to determine whether 786-0 renal cancer cell-derived exosomes promote human umbilical vein endothelial cells (HUVECs) to form tubular structures and to uncover the underlying mechanisms associated with this process. Exosomes were extracted and purified using ultrafiltration and sucrose gradient centrifugation and characterized by transmission electron microscopy. Tubular structure formation was observed using the matrigel tubular assay. In addition, an adenovirus vector was used to transfect the hepatocyte cell adhesion molecule (hepaCAM) gene into renal cancer 786-0 cells. The expression of hepaCAM and vascular endothelial growth factor (VEGF) mRNA and protein was determined by reverse transcription-polymerase chain reaction and western blot analysis, respectively. Tumor cell-derived exosomes were observed to significantly increase tubular formation in HUVECs. Following transfection with the hepaCAM gene, VEGF expression in 786-0 cells was markedly decreased. In HUVECs, exosome treatment increased VEGF mRNA and protein expression, while hepaCAM expression was only decreased at the protein level. In the present study, renal cancer 786-0 cell-derived exosomes significantly promoted angiogenesis via upregulation of VEGF expression in HUVECs, which may be induced by the downregulation of hepaCAM.

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Nanotubes, exosomes, and nucleic acid–binding peptides provide novel mechanisms of intercellular communication in eukaryotic cells: implications in health and disease

Cited by 152 publications

References 32 publications

Functional delivery of viral miRNAs via exosomes

Functional delivery of viral miRNAs via exosomes

MicroRNA126 contributes to granulocyte colony-stimulating factor-induced hematopoietic progenitor cell mobilization by reducing the expression of vascular cell adhesion molecule 1

The 786-0 renal cancer cell-derived exosomes promote angiogenesis by downregulating the expression of hepatocyte cell adhesion molecule

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