Abstract
Growing evidence indicates that intracellular signaling mediated by extracellular vesicles (EVs) released by stem cells plays a considerable role in triggering the regenerative program upon transplantation. EVs from umbilical cord mesenchymal stem cells (UC-MSC-EVs) have been shown to enhance tissue repair in animal models. However, translating such results into clinical practice requires optimized EV collection procedures devoid of animal-originating agents. Thus, in this study, we analyzed the influence of xeno-free expansion media on biological properties of UC-MSCs and UC-MSC-EVs for future applications in cardiac repair in humans. Our results show that proliferation, differentiation, phenotype stability, and cytokine secretion by UC-MSCs vary depending on the type of xeno-free media. Importantly, we found distinct molecular and functional properties of xeno-free UC-MSC-EVs including enhanced cardiomyogenic and angiogenic potential impacting on target cells, which may be explained by elevated concentration of several pro-cardiogenic and pro-angiogenic microRNA (miRNAs) present in the EVs. Our data also suggest predominantly low immunogenic capacity of certain xeno-free UC-MSC-EVs reflected by their inhibitory effect on proliferation of immune cells in vitro. Summarizing, conscious selection of cell culture conditions is required to harvest UC-MSC-EVs with the optimal desired properties including enhanced cardiac and angiogenic capacity, suitable for tissue regeneration.Key messageType of xeno-free media influences biological properties of UC-MSCs in vitro.Certain xeno-free media promote proliferation and differentiation ability of UC-MSCs.EVs collected from xeno-free cultures of UC-MSCs are biologically active.Xeno-free UC-MSC-EVs enhance cardiac and angiogenic potential of target cells.Type of xeno-free media determines immunomodulatory effects mediated by UC-MSC-EVs.
Highlights
The therapeutic potential of mesenchymal stem cells (MSCs) has been widely studied in animal models [1] but wasJ Mol Med (2017) 95:205–220 validated for human patients, indicating efficacy in the treatment of a variety of diseases [2, 3]
Several attempts have already been made to analyze the influence of xeno-free cell culture conditions on the properties of MSCs
Growing evidence indicate similar or superior proliferative capacity as well as maintenance of three-lineage differentiation ability and surface antigen expression of MSCs cultured in xeno-free media compared to standard serumbased conditions [18,19,20,21], which was further supported by our results
Summary
The therapeutic potential of mesenchymal stem cells (MSCs) has been widely studied in animal models [1] but wasJ Mol Med (2017) 95:205–220 validated for human patients, indicating efficacy in the treatment of a variety of diseases [2, 3]. EVs derived from human mesenchymal stem cells (MCS-EVs) were shown to enhance regeneration of various tissues in animal models [10,11,12,13,14,15,16], creating a new treatment option for many disorders. Such therapy could be used to improve regeneration of the infarcted or diseased heart, conditions which are the leading causes of morbidity and mortality worldwide [17], despite the available modalities. To fully translate the beneficial effects of MSC-EVs treatment into the clinic, there is a need to carefully define and standardize cell culture conditions for EVs collection, devoid of any substrates of animal origin
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