Mechanism of TNF-α-Induced Migration and Hepatocyte Growth Factor Production in Human Mesenchymal Stem Cells

Accumulating evidence suggests that mesenchymal stem cells (MSCs) may decrease destructive inflammation and reduce tissue loss. Tumor necrosis factor-alpha (TNF-alpha) plays a central role in induction of proinflammatory signaling and paradoxically activates intracellular anti-inflammatory survival pathways. In this study, we investigated whether TNF-alpha could induce a chemotactic effect on human MSCs and stimulate their production of anti-inflammatory factors in vitro, as well as determined mechanisms that mediated this effect. Migration assays demonstrated that TNF-alpha had a chemotactic effect on MSCs. TNF-alpha increased both hepatocyte growth factor (HGF) mRNA expression in MSCs and HGF secretion in conditioned medium. These effects were dependent on the p38 MAPK and PI3K/Akt, but not JNK and ERK signaling pathways. Furthermore, these effects were inhibited by a specific neutralizing antibody to TNF receptor II, but not TNF receptor I. We conclude that TNF-alpha can enhance human MSCs migration and stimulate their production of HGF. These effects are mediated via a specific TNF receptor and signaling pathways. J. Cell. Biochem. 111: 469-475, 2010. (C) 2010 Wiley-Liss, Inc.