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1 Surgery, Indiana University, Indianapolis, Indiana, United States
2 Urology, Indiana Univ, Indianapolis, Indiana, United States; Physiology and Surgery, Indiana University, Indianapolis, Indiana, United States
3 Surgery, Cellular and Integrative Physiology, and Immunobiology, Indiana University, Indianapolis, Indiana, United States
* To whom correspondence should be addressed. E-mail: dmeldrum{at}iupui.edu.
Accumulating evidence suggests that progenitor cells may decrease destructive inflammation and reduce tissue loss by anti-apoptotic mechanisms. However, they remain poorly characterized, and many questions remain regarding the mechanisms by which they may positively affect wound healing, tissue remodeling or tissue regeneration. Various growth factors have been speculated being responsible, but what components of the wound milieu stimulate progenitor cell production of growth factors, and by what mechanisms? We hypothesized that tumor necrosis factor-
(TNF) stimulated progenitor cell secretion of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and insulin-like growth factor 1 (IGF-1) by a p38 mitogen activated protein kinase (MAPK) dependent mechanism. Human mesenchymal stem cells (hMSCs) and human adipose progenitor cells (hAPCs) were divided into four groups: control, p38 MAPK inhibitor, TNF, and TNF+p38MKI. After 24-hour incubation, supernatants were harvested for VEGF, HGF and IGF-1 assay (ELISA). Cells were collected for measurement of p38 MAPK activation (Western Blot). TNF significantly increased secretion of VEGF, HGF and IGF-1 in hMSCs and hAPCs, which was associated with increased activation of p38 MAPK. The p38 MAPK inhibitor decreased production of TNF-induced VEGF, HGF and IGF-1 in both hMSCs and hAPCs. However, p38 MAPK inhibitor alone had no effect on the production of growth factors. These data demonstrate that progenitor cells are potent sources of VEGF, HGF and IGF-1. TNF, a prominent tissue cytokine, strongly activates hMSCs and hAPCs to produce growth factors by a p38 MAPK dependent mechanism.
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