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1 Surgery, Indiana University, Indianapolis, Indiana, United States
2 Surgery , Indiana University, United States
3 Surgery, Indiana University, United States
4 Physiology and Surgery, Indiana University, Indianapolis, Indiana, United States
* To whom correspondence should be addressed. E-mail: dmeldrum{at}iupui.edu.
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: 1) TNF, LPS, or hypoxia would alter bone marrow mesenchymal stem cell (BMSC) TNF, IGF-1, IL-6, and VEGF production; and 2) TNFR1 or TNFR2 ablation would result in changes to the patterns of cytokines and growth factors produced. BMSCs were harvested from female wildtype, TNFR1KO, and TNFR2KO mice. Cells were stimulated with TNF, LPS or hypoxia. After 24h, cell supernatants were assayed via ELISA. Production of TNF and IGF-1 were decreased in both knockouts compared to WT regardless of the stimulus utilized, while 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 to WT in both knockouts following TNF stimulation, but was significantly decreased with LPS. Compared to WT, hypoxia increased IL-6 in TNFR1KOs, but not in TNFR2KOs. TNF stimulation decreased VEGF in TNFR2KOs, while TNFR1 ablation resulted in no change in VEGF compared to WT. TNFR1 ablation resulted in a decrease in VEGF following LPS stimulation compared to WT; no change was noted in TNFR2KOs. With hypoxia, TNFR1KOs expressed more VEGF compared to WT, while no difference was noted between WT and TNFR2KOs. 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.
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