MEK mediates the novel cross talk between TNFR2 and TGF-EGFR in enhancing vascular endothelial growth factor (VEGF) secretion from human mesenchymal stem cells

Yue Wang, Meijing Wang, Aaron M. Abarbanell, Brent R. Weil, Jeremy L. Herrmann, Jiangning Tan, Nathan M. Novotny, Arthur C. Coffey, Daniel R. Meldrum

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Background: Bone marrow mesenchymal stem cells (MSCs) may mediate their beneficial effects by paracrine mechanisms. Recently, we reported that tumor necrosis factor-alpha (TNF-α) increased the release of vascular endothelial growth factor (VEGF) from human MSCs and augmented transforming growth factor-alpha (TGF-α)-stimulated VEGF secretion. However, it is unknown whether TNF-α stimulates VEGF production via TNF receptor 1 (TNFR1) or 2 (TNFR2) and the mechanism by which TNF-α augments TGF-α (a ligand of epidermal growth factor receptor, EGFR) stimulated VEGF production. We hypothesized that the ablation of TNFR2 would decrease TNF-α-stimulated and/or TGF-α- stimulated VEGF production via MEK-dependent mechanisms. Methods: MSCs transfected with TNFR1, TNFR2, or GAPDH siRNA were stimulated with TNF-α and/or TGF-α for 24 h. VEGF levels in the supernatant were determined by enzyme-linked immunosorbent assay (ELISA). A Western blot analysis was performed to measure the activation of MEK and ERK and the expression of TNFR1 and TNFR2. Results: TNF-α or TGF-α increased VEGF secretion in cells transfected with GAPDH or TNFR1 siRNA. The combination of TNF-α and TGF-α increased VEGF production. TNF-α and/or TGF-α stimulation increased phospho-MEK and phospho-ERK in cells transfected with TNFR1 siRNA. Conversely, the effects of TNF-α and/or TGF-α on MSC VEGF production were significantly decreased, and MEK/ERK activation was negated in cells transfected TNFR2 siRNA. Conclusion: TNFR2 plays a vital role in the effects of TNF-α and TGF-α on MSC VEGF production. The activation of MEK was implicated in this novel cross talk between TNFR2 and TGF-α-EGFR in regulating the production of VEGF in human MSCs.

Original languageEnglish (US)
Pages (from-to)198-205
Number of pages8
JournalSurgery
Volume146
Issue number2
DOIs
StatePublished - Aug 1 2009

ASJC Scopus subject areas

  • Surgery

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