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

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

Submitted 24 April 2008 ; accepted in final form 26 July 2008

Transforming growth factor- (TGF-) 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- stimulates the production of VEGF from MSCs and, if so, by which mechanisms. We hypothesized that TGF- 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-, TNF-, or TGF-+TNF-; 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- dose-response curve demonstrated that low-dose TGF- (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- (250 ng/ml) significantly increased MSC VEGF production (603 ± 24 pg/10⁵ cells/ml). High-dose TGF- also increased TNF--stimulated release of VEGF from MSCs. MSCs exposed to TGF- and/or TNF- also demonstrated increased activation of PI3-K, JNK, and ERK. The TGF--stimulated production of VEGF by MSCs and the additive effect of TNF- and TGF- on VEGF production were abolished by MEK and PI3-K inhibition, but not ERK or JNK inhibition. Our data suggest that TGF- increases VEGF production in MSCs via MEK- and PI3-K- but not ERK- or JNK-dependent mechanisms.

human mesenchymal stem cells; growth factor; MAPK; cellular therapy

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