Paracrine effect of membrane vesicles released by mouse mesoangioblast stem cells on non correlated cell types

Abstract

Introduction Mouse mesoangioblasts are vessel-associated multipotent progenitor stem cells, which are able to differentiate into different mesodermal cell types. In our previous paper we have demonstrated that these cells are able to shed in the extracellular environment membrane vesicles (EV), which contain both structural proteins and biological factors such as FGF2 and the two gelatinases MMP2/9. EV represent an important mediator of cell-to-cell communication and are involved in both autocrine and paracrine signalling. Interestingly, there is a bidirectional signalling exchange between stem cell EV and damaged cells. In particular, EV from injured cells can reprogram stem cells to acquire the phenotype of the damaged tissue or conversely EV from stem cells can induce cell cycle re-entry of resident cells, which can self-repair the tissue. For this reason, we investigated whether EV released by mesoangioblasts interact in a paracrine way with other cell types different from mesoangioblasts, and eventually the effects of this interaction. Results We have already demonstrated that EV were used by mesoangioblasts to release in the extracellular environment the inducible Hsp70. It is inserted within vesicle as a transmembrane protein and is able to interact in a autocrine way with TLR2/4 activating cell migration. Now we have observed that mesoangioblast EV contained a huge amount of mRNA and most of the transcripts are co-expressed in EV and cells, whereas 20 mRNA were accumulated within EV and absent in the cells. Gene ontology analysis showed that the common mRNA could be involved in cell survival and differentiation. We demonstrated that mesoangioblast EV interact with human endothelial ECV304 cells by positively influencing their migration capability. Moreover, they induce in vitro their differentiation versus capillary-like structures depending on their concentration. Mesoangioblast EV are also able to interact with murine macrofages RAW cells inducing dramatic changes in cytokine/chemokine secretion and in RTK phosphorylation levels. Conclusions We demonstrated that mesoangioblast EV are able to interact with both endothelial cells and macrophages influencing their behaviour in terms of migration capability, or cytokine/chemokine secretion and tyrosine kinase receptor phosphorylation. Further studies on EV transcripts could elucidate whether they could be responsible for some of the observed effects. Furthermore, several studies will be directed to evaluate whether these EV are capable of driving differentiation fate of recipient cells.