Prostaglandin E ₂ secreted by mesenchymal stem cells protects against acute liver failure via enhancing hepatocyte proliferation

Abstract

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)E2. Our data confirmed that MSC‐secreted PGE2 not only inhibited apoptosis but also enhanced hepatocyte proliferation, thus attenuating ALF. Moreover, Yes‐associated protein (YAP) played a major role in PGE2‐triggered hepatocyte proliferation. In vitro studies showed that PGE2 increased the expression of PGE4 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 PGE2‐induced hepatocyte proliferation.—Liu, Y., Ren, H., Wang, J., Yang, F., Li, J., Zhou, Y., Yuan, X., Zhu, W., Shi, X. Prostaglandin E2 secreted by mesenchymal stem cells protects against acute liver failure via enhancing hepatocyte proliferation. FASEB J. 33, 2599–2609 (2019). http://www.fasebj.org

Mesenchymal Stem Cells Secreted-Prostaglandin E2 Ameliorates Acute Liver Failure via Attenuation Cell Death and Regulation of Macrophage Polarization

“…Paralyzed with our previous study 13 , MSC protected against ALF through PGE 2 , as revealed by plasma levels of ALT and AST ( Figure 1A) and liver damage in HE staining ( Figure 1B). TUNEL and PI staining con rmed the hepatocyte necrosis and apoptosis was decreased when MSC infusion, especially in MSC-COX2(+) group, however, MSC-COX2(-) failed to decrease hepatocyte necrosis and apoptosis ( Figure 1C and 1D).…”

“…MSC were isolated from 4-to 6-week-old C57BL/6 mice as our previous described 13 . To deplete or overexpress COX2 in MSC to inhibit or increase the synthesis and secretion of PGE 2 , the short hairpin RNA against COX2 or COX2 gene lentivirus (GeneChem, Shanghai, China) was transfected to MSCs following the manufacturer's instructions [named MSC-COX2(-) and MSC-COX2(+)].…”

“…Total RNA or protein for liver tissues and cells were extracted as previous described 13 . The primer sequences and primary antibodies were listed in Supplementary Table S1 and S2.…”

“…Immuno uorescence and HE analyses HE staining analysis of the liver sections were conducted as described previously 13 . The images were captured by a Nikon microscope (Japan).…”

“…Our previous studies showed that MSC-derived PGE 2 promoted hepatocyte proliferation through EP4 13 , we explored whether EP4 also played a role in liver in ammation resolution. We treated mice with EP4 inhibitor (EP4i), GW627368X.…”