Translational Physiology Activation of individual tumor necrosis factor receptors differentially affects stem cell growth factor and cytokine production

Markel TA, Crisostomo PR, Wang M, Herring CM, Meldrum DR. Activation of individual tumor necrosis factor receptors differentially affects stem cell growth factor and cytokine production. Am J Physiol Gastrointest Liver Physiol 293: G657–G662, 2007. First published July 19, 2007; doi:10.1152/ajpgi.00230.2007.—Necrotizing enterocolitis (NEC) is an emergency of the newborn that often requires surgery. Growth factors from stem cells may aid in decreasing intestinal damage while also promoting restitution. We hypothesized that 1) TNF, LPS, or hypoxia would alter bone marrow mesenchymal stem cell (BMSC) TNF, IGF-1, IL-6, and VEGF production, and 2) TNF receptor type 1 (TNFR1) or type 2 (TNFR2) ablation would result in changes to the patterns of cytokines and growth factors produced. BMSCs were harvested from female wild-type (WT), TNFR1 knockout (KO), and TNFR2KO mice. Cells were stimulated with TNF, LPS, or hypoxia. After 24 h, cell supernatants were assayed via ELISA. Production of TNF and IGF-1 was decreased in both knockouts compared with WT regardless of the stimulus utilized, whereas IL-6 and VEGF levels appeared to be cooperatively regulated by both the activated TNF receptor and the initial stimulus. IL-6 was increased compared with WT in both knockouts following TNF stimulation but was significantly decreased with LPS. Compared with WT, hypoxia increased IL-6 in TNFR1KO but not TNFR2KO cells. TNF stimulation decreased VEGF in TNFR2KO cells, whereas TNFR1 ablation resulted in no change in VEGF compared with WT. TNFR1 ablation resulted in a decrease in VEGF following LPS stimulation compared with WT; no change was noted in TNFR2KO cells. With hypoxia, TNFR1KO cells expressed more VEGF compared with WT, whereas no difference was noted between WT and TNFR2KO cells. TNF receptor ablation modifies BMSC cytokine production. Identifying the proper stimulus and signaling cascades for the production of desired growth factors may be beneficial in maximizing the therapeutic potential of stem cells.