Exosomes release

Table 2 is a compilation of 11 proteomic studies of exosomes released by various cells in culture, compared with the data of the complete study done on exosomes collected from urine. Note that of the 22 proteins found in at least 4 of the 11 studies, 20 were also found in urine exosomes. These findings suggest that these proteins are very likely involved in the biogenesis or sorting of molecules in the vesicles. Other proteins are not systematically found in the various studies and might reflect variation between cell types, such as differential expression of cargo proteins. 

Geminard, C., Nault, F., Johnstone, R. and Vidal, M. (2001) Characteristics of the interaction between hsc70 and the transferrin receptor in exosomes released during reticulocyte maturation. J. Biol. Chem. 276,9910-9916. 

Rieu, S., Geminard, C., Rabesandratana, H., Sainte-Marie, J. and Vidal, M. (2000) Exosomes released during reticulocyte maturation bind to fibronectin via integrin a4f l. Eur. J. Biochem. 267, 583-590. Rubinstein, E. (2001) Tetraspanins. Cell Mol. Life Sci. 58, 1189—1205. 

Exosomes can fuse with the target cell, resulting in the nonselective transfer of proteins, RNA, and other signaling molecules to the recipient cell. Exosome uptake from melanoma cells increases in low-pH conditions and is dependent on the presence of sphingomyelin/ganglioside GM3 (Parolini et al., 2009). The fusion efficiency is higher with exosomes released from metastatic cells compared to those derived from primary tumors or normal cells (Parolini et al., 2009). 

MSCs cultured under hypoxic conditions (1% or 3% O2), release exosomes by up to seven-fold more than cells incubated under normoxic conditions (8% O2). These data are consistent with the effects of hypoxia on the release of exosomes from umbilical-cord-derived MSCs, where low oxygen tension increases exosome release by 5.6-fold (Zhang et al., 2012). Hypoxia was also reported to increase the release of exosomes from breast cancer cell lines (MCF7, SKBR3, and MDA-MB 231), squamous carcinoma cells (A431 cells) (Byeon et al., 2010), and... 

Scale-up options include transformation of human MSCs over-expression using the MYC gene. Chen et al. (2011) showed that this transformation produces efficacious exosomes, and is also safe for therapeutic development given the MYC protein was present in the transformed cells but was not detectable in either the conditioned medium or the exosomes. Further, because oncoproteins, unlike the oncogene, cannot be replicated or amplified, possible tumorigenesis by exosomes released from MYC-transformed cells is further reduced. Another possible risk is the use of lentiviral vectors for the transformation of the stem cells, but given that the exosome and not the cell is used for therapy, this risk is also not present. 

In 1996 the exosome was discovered to have an immunological function and consequent study of the immunological role of exosomes has been extensive (Raposo et al., 1996). Exosomes have been shown to take part in both T-cell activation (Sprent, 2005) and in tolerance development (Karlsson et al., 2001). It has been shown that exosomes released from mast cells have the capacity to activate T cells and endothelial cells, and in addition to induce DC maturation. Thus, there is now extensive evidence that exosomes can mediate communication between cells over a distance. Furthermore, exosomes primed with specific tumor antigens are under clinical trials for cancer treatment. 

Atay, S., Gercel-Taylorb, C., Kesimerc, M., Taylor, D.D., 2011. Morphologic and proteo-mic characterization of exosomes released by cultured extravillous trophoblast cells. Exp. Cell Res. Available from http //dx.doi.Org/10.1016/j.yexcr.2011.01.014. 

Riches, A., Campbell, E., Borger, E., Powis, S., 2014. Regulation of exosome release from mammary epithelial and breast cancer cells—a new regulatory pathway. Eur. J. Cancer. 50 (5), 1025—1034. Available from http //dx.doi.0rg/lO.lOl6/j. ejca.2013.12.019. 

Savina, A., Furlan, M., Vidal, M., Colombo, M.I., 2003. Exosome release is regulated by a calcium-dependent mechanism in k562 cells. J. Biol. Chem. 278, 20083—20090. 

Xin, H., Li, Y., Cui, Y., Yang, J.J., Zhang, Z.G., Chopp, M., 2013. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J. Cerebral Blood Flow Metab. 33, 1711-1715, PMID 23963371. 

Llorente, A., Skotland, T., Sylvanne, T, Kauhanen, D., Rog, T., Orlowski, A., Vattulainen, L, Ekroos, K. and Sandvig, K. (2013) Molecular hpidomics of exosomes released by PC-3 prostate caneereeUs. Biochim. Biophys. Acta 1831,1302—1309. 

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