![]() ![]() On the other hand, the protein-rich fraction of the secretome includes different growth factors and cytokines with key roles in the regenerative activity such as vascular endothelial growth factor (VEGF), transforming growth factor β (TGF-β), or hepatocyte growth factor (HGF), among others. ![]() Upon transfer to the receiving cells, they can modulate downstream signaling pathways through the direct stimulation of cell surface receptors or by the direct transfer of bioactive molecules. EV are an integral component of the cell-to-cell communication network, containing a wide range of proteins, lipids, and several coding and noncoding nucleic acids. ĮV are a heterogeneous population of lipid bilayer-delimited particles classified according to their size ( 200 nm) and biogenesis. The secretome can be broadly divided into two fractions: extracellular vesicles (EV) and a wide variety of soluble proteins, lipids, and free nucleic acids. These pro-regenerative effects are not restricted to cell-to-cell effects but can also be reproduced by the secretome of MSC, a wide compendium of bioactive molecules secreted into the extracellular space. These properties intensified the number of preclinical and clinical studies showing the role of adipose stromal/stem cells (ASC) in tissue regeneration. While MSC were first isolated from bone marrow aspirates, other sources such as the adipose tissue have become excellent alternatives due to accessibility and ease of sourcing. Mesenchymal stromal cells (MSC) are considered one of the most promising adult stromal/stem cell types in regenerative cell-based therapies. Specific ASC-EV effects need to be dissected for their use as cell-free therapeutics. Our data indicate that the effects of ASC on immunomodulation and angiogenesis are EV-independent. Within the secretome/protein fraction, VEGF was identified as a potential driver of angiogenesis, and was absent in both EV preparations. ![]() In turn, tube formation and wound healing were strongly promoted by the ASC secretome and protein fraction, but not by EV. However, EV generated by SEC stimulated macrophage phagocytic activity to a similar extent as the secretome. In the current study, neither the EV preparations, the secretome or the protein fraction were efficacious in inhibiting mitogen-driven T cell proliferation. The effect of both EV preparations on immunomodulation and angiogenesis in vitro was compared to that of the whole secretome and of the EV-free protein fraction after SEC isolation. To answer this question, we performed an inter-laboratory study evaluating EV generated from adipose stromal cells (ASC) by either sequential ultracentrifugation (UC) or size-exclusion chromatography (SEC). We hypothesized that this discrepancy may depend either on the method of isolation or rather the relative impact of the individual bioactive components within the MSC secretome. Numerous reports describe the efficacy of EV in conferring immunomodulation and promoting angiogenesis, yet others report these activities to be conveyed in EV-free bioproducts. Extracellular vesicles (EV) are considered a cell-free alternative to mesenchymal stromal cell (MSC) therapy.
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