Prostaglandin E2 secreted by mesenchymal stem cells protects against acute liver failure via enhancing hepatocyte proliferation

Bone marrow-derived mesenchymal stem cells (MSCs) have been recently used in clinical trials as treatment for liver diseases. However, the underlying mechanism of their effectiveness remains largely unexplored. In the present study, we confirmed that the protective effects of MSCs on mouse model of acute liver failure (ALF) were based on MSC-secreted prostaglandin (PG)E-2. Our data confirmed that MSC-secreted PGE(2) not only inhibited apoptosis but also enhanced hepatocyte proliferation, thus attenuating ALF. Moreover, Yes-associated protein (YAP) played a major role in PGE(2)-triggered hepatocyte proliferation. In vitro studies showed that PGE(2) increased the expression of PGE(4) and enhanced the phosphorylation of cAMP response element binding protein, resulting in YAP activation and increased expression of YAP-related genes. Furthermore, the mammalian target of rapamycin, another major regulator of cell proliferation, was activated by YAP via suppressing phosphatase and tensin homolog through miR-29a-3p. These pathways coordinated to control cell proliferation. Collectively, MSCs could promote the recovery of ALF through PGE(2)-induced hepatocyte proliferation.Liu, Y., Ren, H., Wang, J., Yang, F., Li, J., Zhou, Y., Yuan, X., Zhu, W., Shi, X. Prostaglandin E-2 secreted by mesenchymal stem cells protects against acute liver failure via enhancing hepatocyte proliferation.