TGF-α increases human mesenchymal stem cell-secreted VEGF by MEK- and PI3-K- but not JNK- or ERK-dependent mechanisms

Yue Wang, Paul R. Crisostomo, Meijing Wang, Troy A. Markel, Nathan M. Novotny, Daniel R. Meldrum

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Transforming growth factor-α (TGF-α) may be an important mediator of wound healing and the injury response. Human bone marrow mesenchymal stem cells (MSCs) release VEGF as a potentially beneficial paracrine response; however, it remains unknown whether TGF-α stimulates the production of VEGF from MSCs and, if so, by which mechanisms. We hypothesized that TGF-α would increase human MSC VEGF production by MAP kinase kinase (MAPKK/MEK), phosphatidylinositol 3-kinase (PI3-K)-, ERK, and JNK-dependent mechanisms. To study this, MSCs were cultured and divided into the following groups: 1) with vehicle; 2) with various stimulants alone: TGF-α, TNF-α, or TGF-α+TNF-α; 3) with individual kinase inhibitors alone (two different inhibitors for each of the following kinases: MEK, PI3-K, ERK, or JNK); and 4) with the above stimulants and each of the eight inhibitors. After 24-h incubation, a TGF-α dose-response curve demonstrated that low-dose TGF-α (500 pg/ml) suppressed MSC production of VEGF compared with vehicle (502 ± 16 pg/105 cells/ml to 332 ± 9 pg/105 cells/ml), while high-dose TGF-α (250 ng/ml) significantly increased MSC VEGF production (603 ± 24 pg/105 cells/ml). High-dose TGF-α also increased TNF-α-stimulated release of VEGF from MSCs. MSCs exposed to TGF-α and/or TNF-α also demonstrated increased activation of PI3-K, JNK, and ERK. The TGF-α-stimulated production of VEGF by MSCs and the additive effect of TNF-α and TGF-α on VEGF production were abolished by MEK and PI3-K inhibition, but not ERK or JNK inhibition. Our data suggest that TGF-α increases VEGF production in MSCs via MEK- and PI3-K- but not ERK- or JNK-dependent mechanisms.

Original languageEnglish (US)
Pages (from-to)R1115-R1123
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume295
Issue number4
DOIs
StatePublished - Oct 1 2008

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Keywords

  • Cellular therapy
  • Growth factor
  • Human mesenchymal stem cells
  • MAPK

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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