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Extracellular vesicles (EV) are small plasma membrane-derived particles released into the extracellular space by virtually all cell types. Recently, EV have received increased interest because of their capability to carry nucleic acids, proteins, lipids and signaling molecules and to transfer their cargo into the target cells. Less attention has been paid to their role in modifying the composition of the extracellular matrix (ECM), either directly or indirectly via regulating the ability of target cells to synthesize or degrade matrix molecules. Based on recent results, EV can be considered one of the structural and functional components of the ECM that participate in matrix organization, regulation of cells within it, and in determining the physical properties of soft connective tissues, bone, cartilage and dentin. This review addresses the relevance of EV as specific modulators of the ECM, such as during the assembly and disassembly of the molecular network, signaling through the ECM and formation of niches suitable for tissue regeneration, inflammation and tumor progression. Finally, we assess the potential of these aspects of EV biology to translational medicine., (Copyright © 2017 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.)

Extracellular vesicles (EVs) secreted by stem cells are potential factors mediating tissue regeneration. They travel from bone marrow stem cells into damaged tissues, suggesting that they can repair tissue injuries without directly replacing parenchymal cells. We have discovered that hyaluronan (HA) synthesis is associated with the shedding of HA-coated EVs. The aim of this study was to test whether bone marrow-derived hMSCs secrete HA-coated EVs. The EVs secreted by MSCs were isolated by differential centrifugation and characterized by nanoparticle tracking analysis. Their morphology and budding mechanisms were inspected by confocal microscopy and correlative light and electron microscopy. Hyaluronan synthesis of hMSCs was induced by lipopolysaccharide and inhibited by RNA interference and 4-methylumbelliferone. It was found that the MSCs have extremely long apical and lateral HA-coated filopodia, typical for cells with an active HA secretion. Additionally, they secreted HA-coated EVs carrying mRNAs for CD44 and all HAS isoforms. The results show that stem cells have a strong intrinsic potential for HA synthesis and EV secretion, and the amount of HA carried on EVs reflects the HA content of the original cells. These results show that the secretion of HA-coated EVs by hMSCs is a general process, that may contribute to many of the mechanisms of HA-mediated tissue regeneration. Additionally, an HA coat on EVs may regulate their interactions with target cells and participate in extracellular matrix remodeling., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The mesothelium is a membrane that forms the lining of several body cavities. It is composed of simple squamous mesothelial cells that secrete a glycosaminoglycan-rich lubricating fluid between inner organs. One of the most abundant glycosaminoglycans of those fluids is hyaluronan, which is synthesized on a plasma membrane and especially on apical filopodia of cultured cells. Our recent study showed that similar hyaluronan-rich protrusions are found in mesothelial lining in vivo, which suggests that hyaluronan synthesis in plasma membrane protrusions is a general process. However, the mesothelial lining was negative for the hyaluronan receptor CD44 while in many previous studies cultured mesothelial cells have been shown to express CD44. To further explore these findings we induced epithelial to mesenchymal transition in primary rat mesothelial cells by EGF-treatment and scratch wounding. Surprisingly, the results showed that at a normal epithelial, confluent stage the mesothelial cells are negative for CD44, but EMT induced by EGF or wounding activates CD44 expression and the whole hyaluronan synthesis machinery. In addition to typical EMT-like morphological changes, the growth of apical filopodia and budding of extracellular vesicles (EVs) were induced. In summary, the results of this study show that the activation of hyaluronan synthesis machinery, especially the expression of CD44 is strongly associated with EMT induced by EGF and wounding in mesothelial cells. Moreover, EMT enhances the secretion of EVs that carry CD44 and hyaluronan, which may be important regulators in EV interactions with their targets and ECM remodeling. The results of the present study also suggest that CD44 is a potential marker for EVs, especially those secreted from cells during tissue repair and pathological processes., (Copyright © 2016 Elsevier B.V. All rights reserved.)