In the light of above findings, herein, we propose that the mechanism of priming of MSC could be implied to the following: i) Licensing by pro-inflammatory cytokines such as IFN-γ, TNF-α, etc., to enhance immunosuppressive potential; ii) Priming by non-cytokines stimuli such as hormones/growth factors like HGF to boost defensive and protective cellular mechanisms; iii) Pre-conditioning by hypoxia, and/or pharmacological agents, e.g., sphingosine-1-phosphate, etc., to enhance engraftment and reparative effects; iv) Activation by spheroid culturing to enhance homing, survival, differentiation, and lineage specificity e.g. angiogenic mechanism; v) The timing of MSCs engraftment and engagement in the process of activation of immune cells to achieve the most excellent beneficial effect of MSCs infusion.