期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 294, 期 3, 页码 C675-C682出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00437.2007
关键词
vascular endothelial growth factor; fibroblast growth factor 2; hepatocyte growth factor; insulin-like growth factor 1; mitogen-activated protein kinase
资金
- NHLBI NIH HHS [R01HL-085595, F32HL-085982, K99/R00 HL-0876077] Funding Source: Medline
- NIGMS NIH HHS [R01GM-070628] Funding Source: Medline
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 tumor necrosis factor-alpha (TNF-alpha), endotoxin (LPS), or hypoxia may activate human mesenchymal stem cells (MSCs) to increase release of vascular endothelial growth factor ( VEGF), fibroblast growth factor 2 (FGF2), insulin-like growth factor 1 (IGF-1), or hepatocyte growth factor (HGF) and that nuclear factor-kappa B (NF kappa B), c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) mediates growth factor production from human MSCs. To study this, human MSCs were harvested, passaged, divided into four groups ( 100,000 cells, triplicates) and treated as follows: 1) with vehicle; 2) with stimulant alone [ 24 h LPS ( 200 ng/ml), 24 h TNF-alpha ( 50 ng/ml), or 24 h hypoxia ( 1% O-2)]; 3) with inhibitor alone [NF kappa B ( PDTC, 1 mM), JNK (TI-JIP, 10 mu M), or ERK ( ERK Inhibitor II, 25 mu M)]; and 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-alpha, LPS, and hypoxia significantly increased human MSC VEGF, FGF2, HGF, and IGF-1 production versus controls. Stem cells exposed to injury demonstrated increased activation of NF kappa B, ERK, and JNK. VEGF, FGF2, and HGF expression was significantly reduced by NF kappa B inhibition (50% decrease) but not ERK or JNK inhibition. Moreover, ERK, JNK, and NF kappa B 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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