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This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/C1284    most recent 00183.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wang, Y. Articles by Meldrum, D. R. PubMed PubMed Citation Articles by Wang, Y. Articles by Meldrum, D. R.

Receptors and Signal Transduction

MEK, p38, and PI-3K mediate cross talk between EGFR and TNFR in enhancing hepatocyte growth factor production from human mesenchymal stem cells

¹Clarian Cardiovascular Surgery, Departments of ²Surgery and ³Cellular and Integrative Physiology, and ⁴Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana

Submitted 28 April 2009 ; accepted in final form 19 August 2009

Human bone marrow mesenchymal stem cells (MSCs) are a potent source of growth factors, which are partly responsible for their beneficial paracrine effects. We reported previously that transforming growth factor- (TGF-), a putative mediator of wound healing and the injury response, increases the release of vascular endothelial growth factor (VEGF), augments tumor necrosis factor- (TNF-)-stimulated VEGF production, and activates mitogen-activated protein kinases and phosphatidylinositol 3-kinase (PI-3K) pathway in human MSCs. The experiments described in this report indicate that TGF- increases MSC-derived hepatocyte growth factor (HGF) production. TGF--stimulated HGF production was abolished by inhibition of MEK, p38, PI-3K, or by small interfering RNA (siRNA) targeting TNF receptor 2 (TNFR2), but was not attenuated by siRNA targeting TNF receptor 1 (TNFR1). Ablation of TNFR1 significantly increased basal and stimulated HGF. A potent synergy between TGF- and TNF- was noted in MSC HGF production. This synergistic effect was abolished by MEK, P38, PI-3K inhibition, or by ablation of both TNF receptors using siRNA. We conclude that 1) novel cross talk occurs between tumor necrosis factor receptor and TGF-/epidermal growth factor receptor in stimulating MSC HGF production; 2) this cross talk is mediated, at least partially, via activation of MEK, p38, and PI-3K; 3) TGF- stimulates MSCs to produce HGF by MEK, p38, PI-3K, and TNFR2-dependent mechanisms; and 4) TNFR1 acts to decrease basal TGF- and TNF--stimulated HGF.

transforming growth factor-; vascular endothelial growth factor; tumor necrosis factor-; epidermal growth factor receptor; phosphatidylinositol 3-kinase; tumor necrosis factor receptor