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Itinerant exosomes: Emerging roles in cell and tissue polarity

Margaret M. Dyson Vision Research Institute, Department of Ophthalmology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Trends in cell biology (Impact Factor: 12.31). 06/2008; 18(5):199-209. DOI: 10.1016/j.tcb.2008.03.002
Source: PubMed

ABSTRACT Cells use secreted signals (e.g. chemokines and growth factors) and sophisticated vehicles such as argosomes, cytonemes, tunneling nanotubes and exosomes to relay important information to other cells, often over large distances. Exosomes, 30-100-nm intraluminal vesicles of multivesicular bodies (MVB) released upon exocytic fusion of the MVB with the plasma membrane, are increasingly recognized as a novel mode of cell-independent communication. Exosomes have been shown to function in antigen presentation and tumor metastasis, and in transmitting infectious agents. However, little is known about the biogenesis and function of exosomes in polarized cells. In this review, we discuss new evidence suggesting that exosomes participate in the transport of morphogens and RNA, and thus influence cell polarity and developmental patterning of tissues.

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Available from: Aparna Lakkaraju, Jul 09, 2014
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    • "A member of the RAB GTPase family, RAB5, is a key regulator of endocytic trafficking and acts as a molecular switch by cycling active GTP-and inactive GDP-bound states. In the animal system, RAB5 is well characterized and regulates various endosomal functions (Somsel Rodman and Wandinger-Ness 2000, Benmerah 2004, Russell et al. 2006, Lakkaraju and Rodriguez-Boulan 2008, Villarroel-Campos et al. 2014). Plants also harbor orthologs of animal RAB5; in addition, land plants harbor the plant-unique RAB5 group, the ARA6 group (Ueda et al. 2001, Ebine et al. 2011). "
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    ABSTRACT: Endosomal trafficking plays integral roles in various eukaryotic cell activities. In animal cells, a member of the RAB GTPase family, RAB5, is a key regulator of various endosomal functions. In addition to orthologs of animal RAB5, plants harbor the plant-specific RAB5 group, the ARA6 group, which is conserved in land plant lineages. In Arabidopsis thaliana, ARA6 and conventional RAB5 act in distinct endosomal trafficking pathways; ARA6 mediates trafficking from endosomes to the plasma membrane, whereas conventional RAB5 acts in endocytic and vacuolar trafficking pathways. ARA6 is also required for normal salt and osmotic stress tolerance, although the functional link between ARA6 and stress tolerance remains unclear. In this study, we investigated ARA6 function in stress tolerance by monitoring broad-scale changes in gene expression in the ara6 mutant. A comparison of the expression profiles between wild-type and ara6-1 plants revealed that the expression of the Qua-Quine Starch (QQS) gene was significantly affected by the ara6-1 mutation. QQS is involved in starch homeostasis, consistent with the starch content decreasing in the ara6 mutants to approximately 60% of that of the wild-type plant. In contrast, the free and total glucose content increased in the ara6 mutants. Moreover, the proliferation of Pseudomonas syringae pv. tomato DC3000 was repressed in ara6 mutants, which could be attributed to the elevated sugar content. These results suggest that ARA6 is responsible for starch and sugar homeostasis, most likely through the function of QQS. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    Plant and Cell Physiology 02/2015; 56(6). DOI:10.1093/pcp/pcv029 · 4.98 Impact Factor
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    • "Exosomes also harbor mRNA and miRNA [18], where the delivery of miRNA may be the most important factor in target cell modulation [18] [19] [20] [21]. Nonetheless, the exosomal membrane takes over an important function in binding and uptake by selected target cells, where exosomal annexins, adhesion molecules, and tetraspanins are involved [13] [22] [23]. For dendritic cells, it is known that they can be replaced by exosomes, which provide peptide-loaded major histocompatibility complex (MHC) and co-stimulatory molecules Abbreviations: ASML, BSp73ASML; ASML-CD44v kd [24] [25] and exosomal heat shock proteins that support non-adaptive immune responses [26] [27]. "
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    ABSTRACT: Exosomes are important intercellular communicators, where tumor exosomes (TEX) severely influence hematopoiesis and premetastatic organ cells. With the extracellular matrix (ECM) being an essential constituent of non-transformed tissues and tumors, we asked whether exosomes from a metastatic rat tumor also affect the organization of the ECM and whether this has consequences on host and tumor cell motility. TEX bind to individual components of the ECM, the preferential partner depending on the exosomes' adhesion molecule profile such that high CD44 expression is accompanied by hyaluronic acid binding and high α6β4 expression by laminin (LN) 332 binding, which findings were confirmed by antibody blocking. TEX can bind to the tumor matrix already during exosome delivery but also come in contact with distinct organ matrices. Being rich in proteases, TEX modulate the ECM as demonstrated for degradation of collagens, LNs, and fibronectin. Matrix degradation by TEX has severe consequences on tumor and host cell adhesion, motility, and invasiveness. By ECM degradation, TEX also promote host cell proliferation and apoptosis resistance. Taken together, the host tissue ECM modulation by TEX is an important factor in the cross talk between a tumor and the host including premetastatic niche preparation and the recruitment of hematopoietic cells. Reorganization of the ECM by exosomes likely also contributes to organogenesis, physiological and pathologic angiogenesis, wound healing, and clotting after vessel disruption.
    Neoplasia (New York, N.Y.) 08/2013; 15(8):875-87. DOI:10.1593/neo.13786 · 5.40 Impact Factor
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    • "Exosomal microRNA (miRNA) in serum is also discussed as a potential marker for tumor diagnosis [17] [18]. Exosomes, small vesicles delivered by many cells and abundantly by tumor cells [19], derive from early endosomes, which fuse to multivesicular bodies (MVBs), from where individual vesicles (exosomes) are released in the extracellular space [20] [21] [22] [23]. Accordingly, exosomes are rich in proteins located in internalization-prone membrane domains and molecules engaged in fission, scission, and vesicular transport [14] [22] [24] [25]. "
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    ABSTRACT: Tumor exosomes educate selected host tissues toward a prometastatic phenotype. We demonstrated this for exosomes of the metastatic rat adenocarcinoma BSp73ASML (ASML), which modulate draining lymph nodes and lung tissue to support settlement of poorly metastatic BSp73ASML-CD44v4-v7 knockdown (ASML-CD44v) cells. Now, we profiled mRNA and microRNA (miRNA) of ASML and ASML-CD44v exosomes to define the pathway(s), whereby exosomes prepare the premetastatic niche. ASML exosomes, recovered in draining lymph nodes after subcutaneous injection, preferentially are taken up by lymph node stroma cells (LnStr) and lung fibroblasts (LuFb) that were chosen as exosome targets. ASML and ASML-CD44v exosomes contain a restricted mRNA and miRNA repertoire that differs significantly between the two lines and exosomes thereof due to CD44v6 influencing gene and miRNA transcription/posttranscriptional regulation. Exosomal mRNA and miRNA are recovered in target cells, where transferred miRNA significantly affected mRNA translation. Besides others, this was exemplified for abundant ASML-exosomal miR-494 and miR-542-3p, which target cadherin-17 (cdh17). Concomitantly, matrix metalloproteinase transcription, accompanying cdh17 down-regulation, was upregulated in LnStr transfected with miR-494 or miR-542-3p or co-cultured with tumor exosomes. Thus, tumor exosomes target non-transformed cells in premetastatic organs and modulate premetastatic organ cells predominantly through transferred miRNA, where miRNA from a metastasizing tumor prepares premetastatic organ stroma cells for tumor cell hosting. Fitting the demands of metastasizing tumor cells, transferred exosomal miRNA mostly affected proteases, adhesion molecules, chemokine ligands, cell cycle- and angiogenesis-promoting genes, and genes engaged in oxidative stress response. The demonstration of function-competent exosomal miRNA in host target cells encourages exploiting exosomes as a therapeutic gene delivery system.
    Neoplasia (New York, N.Y.) 03/2013; 15(3):281-95. DOI:10.1593/neo.122010 · 5.40 Impact Factor
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