Such cell lines may be modified to obtain ExMVs that do not express HLA antigens (a), are enriched in growth factors, cytokines, chemokines and bioactive lipids that promote regeneration of damaged organs (b), are enriched in mRNA and regulatory miRNA facilitating regeneration of damaged tissues and/or promoting angiogenesis (c), or display on their surface molecules that direct them to, and cause them to be retained in, damaged tissues (d) (adapted from Ratajczak et al. the existence of the horizontal transfer of RNA. Moreover, in addition to RNA, proteins, bioactive lipids, infectious particles and intact organelles such as mitochondria may follow a similar mechanism. In this review we will summarize the impressive progress in this field14?years shikonofuran A after initial report. strong class=”kwd-title” Keywords: RNA, ExMVs, Horizontal transfer of RNA, Exosomes, Regenerative medicine, Circulating RNA, Liquid biopsies Introduction Both single-celled organisms (e.g., bacteria, protozoea) and cells that are shikonofuran A part of multicellular organisms communicate with the environment and other cells by several mechanisms. The best known and studied so far are ligandCreceptor-based interactions that involve peptides, bioactive lipids, extracellular nucleotides, and the corresponding specific receptors on the cell surface or in the cell cytoplasm that bind these ligands. Interestingly, evidence has accumulated that the one of most developmentally early cell-to-cell communication mechanism involves spherical membrane fragments shed from the cell surface or the endosomal compartment, which have been described collectively as microparticles, microvesicles, or exosomes [1C5]. This communication mechanism is preserved in all species, and small spherical membrane fragments are currently called extracellular microvesicles (ExMVs), as recommended by the International Society for Extracellular Vesicles [2]. While larger ExMVs (~100?nmC1?m in diameter) are shed from lipid raft-enriched cell surface membrane domains by blebbing and budding of the cell membrane, smaller ExMVs (~40C150?nm), also known as exosomes, are derived from the endosomal cell membrane compartment and originate from multivesicular bodies (MVBs) or from the release of Golgi apparatus-derived vesicles in the process of exocytosis (Fig.?1) [1C6]. Whatever their source, ExMVs that are released from normal healthy cells should be distinguished from apoptotic bodies that originate in dying cells. It is important to keep in mind this difference, because some small apoptotic bodies could be co-isolated with ExMVs [2]. Open in a separate window Fig.?1 Upon activation, every cell type secretes ExMVs. Larger ExMVs (microvesicles) are released from the cell surface by blebbing and budding of the cell membrane, Smaller ExMVs (exosomes) are initiated in endosomes as intraluminal vesicles in multivesicular bodies (MVBs) after endocytosis of pathogens or due to activation of cells by other stimuli, or are generated in the Golgi apparatus during secretion of cell-synthesized proteins The fact that ExMVS are present in biological fluids or in conditioned media harvested from cells cultured in vitro has been known for many years, and it has been suggested step by step by some investigators that these small spherical membrane constructions play an important role in several biological processes. For example, peripheral blood platelet-derived ExMVs have been demonstrated to be shikonofuran A involved in the coagulation process [7], mesenchymal stromal cell (MSC)-derived ExMVs in bone mineralization [8], and B cell-derived ExMVs in rules of particular T cell-mediated immune responses [9]. However, for many years there was skepticism about the part of these membrane fragments in regulating cells, and they were often dismissed as cell debris released from damaged cells. Thus, many of the biological effects of ExMVs were considered to be artifacts, and it required a while to convince the medical community that ExMVs may be released from normal healthy cells. Now it seems likely the trafficking of ExMVs was one of the 1st cell-to-cell communication mechanisms that emerged during development and anticipated the development of more specific ligand-receptor relationships [1C6]. Following on this concept, some papers have been published showing that ExMVs act as signaling device and activate target cells by ligands indicated within the ExMV surface [10, 11] or from the shikonofuran A transfer of membrane receptors from one cell to another [12]. However, one of the major problems with moving this field ahead has been the lack of established methods to isolate, measure the concentration of, and purify ExMVs from biological fluids. Some of these problems remain today, and several methods have been proposed to unify isolation and enumeration protocols [2]. The most likely explanation for the quick development of ExMV study, which has been followed by an exponential increase in the number of published papers in subsequent years, has been the demonstration that these small cellular membrane fragments transfer RNA varieties and several additional biologically active molecules between cells and thus may induce practical changes in the prospective cells [13C15]. These observations became particularly important at p53 the time of finding of stem cell plasticity, when some of the markers.