Heterogeneity of mesenchymal stem cell-derived extracellular vesicles is highly impacted by the tissue/cell source and culture conditions

Abstract

Extracellular vesicles (EVs) are cell-derived membrane structures exerting major effects in physiological as well as pathological processes by functioning as vehicles for the delivery of biomolecules to their target cells. An increasing number of effects previously attributed to cell-based therapies have been recognized to be actually mediated by EVs derived from the respective cells, suggesting the administration of purified EVs instead of living cells for cell-based therapies. In this review, we focus on the heterogeneity of EVs derived from mesenchymal stem/stromal cells (MSC) and summarize upstream process parameters that crucially affect the resulting therapeutic properties and biological functions. Hereby, we discuss the effects of the cell source, medium composition, 3D culture, bioreactor culture and hypoxia. Furthermore, aspects of the isolation and storage strategies influences EVs are described. Conclusively, optimization of upstream process parameters should focus on controlling MSC-derived EV heterogeneity for specific therapeutic applications. Graphical Abstract

Mesenchymal stem cell culture within perfusion bioreactors incorporating 3D-printed scaffolds enables improved extracellular vesicle yield with preserved bioactivity

“…We found that the same bioactivity pattern was apparent when using bone marrow-derived MSC EVs from several donors, but not when using MSC EVs derived from adipose tissue ( Figure S3 ). This emphasizes the impact and importance of choosing the optimal EV source for the desired application [62]. The observed similarity in angiogenic activity between the flask- and bioreactor-derived MSC EVs were supported by similar cellular uptake of the EVs by HUVECs and comparable surface protein fingerprints ( Figure 6B, D ).…”

Comparative Analysis of Natural and Cytochalasin B-Induced Membrane Vesicles from Tumor Cells and Mesenchymal Stem Cells

“…MSC-derived EVs are part of the stem cell secretome and play an important role in mediating the effects of stem cells on the other cells of the body. Moreover, cell-free therapy using EVs can circumvent the disadvantages associated with cell-based therapy, namely poor cell survival upon administration, morphological, and functional changes during therapy, and the possibility of differentiation into undesirable cell types [ 19 ].…”

“…Various mechanisms of EV uptake have been proposed in the literature, including phagocytosis or fusion of EVs with the plasma membrane of recipient cells. In addition, cells can provide selective uptake of EVs depending on the repertoire of their surface receptors [ 19 ]. We have shown that NEVs and CIMVs from MSCs and SNB-19 cells can be uptaken by MCF-7 and HCT-15 cells.…”

Optimizing repair of tendon ruptures and chronic tendinopathies: Integrating the use of biomarkers with biological interventions to improve patient outcomes and clinical trial design

“…These EV or exosomes are shed or released from cells and can contain a variety of growth regulating molecules including proteins and miRNAs (68)(69)(70)(71). The contents of such EV or exosome can be influenced by the culture conditions of the cells of origin (72,73). EV would have to be taken up by endogenous cells and exert an anabolic effect to foster repair of an injured tendon, or perhaps modify cells contributing to a catabolic environment such as macrophages (69).…”