PGE2 maintains self-renewal of human adult stem cells via EP2-mediated autocrine signaling and its production is regulated by cell-to-cell contact

Mesenchymal stem cells (MSCs) possess unique immunomodulatory abilities. Many studies have elucidated the clinical efficacy and underlying mechanisms of MSCs in immune disorders. Although immunoregulatory factors, such as Prostaglandin E-2 (PGE(2)), and their mechanisms of action on immune cells have been revealed, their effects on MSCs and regulation of their production by the culture environment are less clear. Therefore, we investigated the autocrine effect of PGE(2) on human adult stem cells from cord blood or adipose tissue, and the regulation of its production by cell-to-cell contact, followed by the determination of its immunomodulatory properties. MSCs were treated with specific inhibitors to suppress PGE(2) secretion, and proliferation was assessed. PGE(2) exerted an autocrine regulatory function in MSCs by triggering E-Prostanoid (EP) 2 receptor. Inhibiting PGE(2) production led to growth arrest, whereas addition of MSC-derived PGE(2) restored proliferation. The level of PGE(2) production from an equivalent number of MSCs was down-regulated via gap junctional intercellular communication. This cell contact-mediated decrease in PGE(2) secretion down-regulated the suppressive effect of MSCs on immune cells. In conclusion, PGE(2) produced by MSCs contributes to maintenance of self-renewal capacity through EP2 in an autocrine manner, and PGE(2) secretion is down-regulated by cell-to-cell contact, attenuating its immunomodulatory potency.