Abstract
Cells release extracellular vesicles (EVs) to communicate in a paracrine manner with other cells, and thereby influence processes, such as angiogenesis. The conditioned medium of human cardiac-derived adherent proliferating (CardAP) cells was recently shown to enhance angiogenesis. To elucidate whether their released EVs are involved, we isolated them by differential centrifugation from the conditioned medium derived either in the presence or absence of a pro-inflammatory cytokine cocktail. Murine recipient cells internalized CardAP-EVs as determined by an intracellular detection of human proteins, such as CD63, by a novel flow cytometry method for studying EV–cell interaction. Moreover, endothelial cells treated for 24 h with either unstimulated or cytokine stimulated CardAP-EVs exhibited a higher tube formation capability on Matrigel. Interestingly, unstimulated CardAP-EVs caused endothelial cells to release significantly more vascular endothelial growth factor and interleukin (IL)-6, while cytokine stimulated CardAP-EVs significantly enhanced the release of IL-6 and IL-8. By nCounter® miRNA expression assay (NanoString Technologies) we identified microRNA 302d-3p to be enhanced in unstimulated CardAP-EVs compared to their cytokine stimulated counterparts, which was verified by quantitative polymerase chain reaction. This study demonstrates that both CardAP-EVs are pro-angiogenic by inducing different factors from endothelial cells. This would allow to select potent targets for a safe and efficient therapeutic application.
Highlights
Cell-cell communication between neighboring and distant cells is crucial for the survival of an organism
We focused on the interaction between cardiac-derived adherent proliferating (CardAP)-extracellular vesicles (EVs) and cardiovascular target cells to determine their impact on angiogenesis as a means to further evaluate their potential as a tool for treating heart diseases
Since the function of EVs can be strongly influenced by the microenvironment they experience during their biogenesis [32,47], we modulated the milieu of well-characterized regenerative cardiac cells to gather insights into how those changes might affect the pro-angiogenic features of their released EVs
Summary
Cell-cell communication between neighboring and distant cells is crucial for the survival of an organism. A direct communication between neighboring cells is ensured by structural connections between them, like tight junctions, while it is enabled in an indirect manner by releasing signaling molecules into the extracellular space [1,2,3,4,5]. Knowledge about mechanisms triggered by this cellular crosstalk can help to improve or even to evolve new therapeutic approaches Processes such as angiogenesis, are highly desired to be enhanced for treating diseases, like those of the cardiovascular system [6,7]. For example, have altered their communication to facilitate the formation of metastases and to evade immune responses [8,9]
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