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1 Surgery, Indiana University, Indianapolis, Indiana, United States
2 Surgery, Indiana University, United States
3 Indiana University, Indiana, United States
4 Physiology and Surgery, Indiana University, Indianapolis, Indiana, United States
* To whom correspondence should be addressed. E-mail: dmeldrum{at}iupui.edu.
Understanding the mechanisms by which adult stem cells produce growth factors may represent an important way to optimize their beneficial paracrine and autocrine effects. Components of the wound milieu may stimulate growth factor production to promote stem cell mediated repair. We hypothesized that TNF, endotoxin (LPS), or hypoxia may activate human mesenchymal stem cells (MSCs) to increase release of VEGF, FGF2, IGF-1, or HGF, and that NFKB, JNK, and ERK mediates growth factor production from human MSCs. To study this, human MSCs were harvested, passaged, divided into 4 groups (100,000 cells, triplicates), and treated as follows: 1) with vehicle; 2) with stimulant alone: 24 hr LPS (200 ng / ml), 24 hr TNF (50 ng / ml), or 24 hr hypoxia (1.0% O2); 3) with inhibitor alone: NFkB (PDTC 1 mM), JNK (TI-JIP10 uM), or ERK (ERK Inhibitor II 25 uM); 4) with stimulant and the various inhibitors. After 24 h incubation, MSC activation was determined by measuring supernatants for VEGF, FGF2, IGF-1, or HGF (ELISA). TNF, LPS, and hypoxia significantly increased human MSC VEGF, FGF2, HGF, and IGF-1 production vs controls. Stem cells exposed to injury demonstrated increased activation of NFkB, ERK, and JNK. VEGF, FGF2, and HGF expression was significantly reduced by NFkB inhibition (50% decrease) but not ERK or JNK inhibition. Moreover, ERK, JNK and NFkB inhibitor alone did not activate MSC VEGF expression over controls. Various stressors activate human MSCs to increase VEGF, FGF2, HGF, and IGF-1 expression which depends on an NFkB mechanism.
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