Growth factor regulation of prostaglandin-endoperoxide synthase 2 (Ptgs2) expression in colonic mesenchymal stem cells.
ABSTRACT We previously found that a population of colonic stromal cells that constitutively express high levels of prostaglandin-endoperoxide synthase 2 (Ptgs2, also known as Cox-2) altered their location in the lamina propria in response to injury in a Myd88-dependent manner (Brown, S. L., Riehl, T. E., Walker, M. R., Geske, M. J., Doherty, J. M., Stenson, W. F., and Stappenbeck, T. S. (2007) J. Clin. Invest. 117, 258-269). At the time of this study, the identity of these cells and the mechanism by which they expressed high levels of Ptgs2 were unknown. Here we found that these colonic stromal cells were mesenchymal stem cells (MSCs). These colonic MSCs expressed high Ptgs2 levels not through interaction with bacterial products but instead as a consequence of mRNA stabilization downstream of Fgf9 (fibroblast growth factor 9), a growth factor that is constitutively expressed by the intestinal epithelium. This stabilization was mediated partially through a mechanism involving endogenous CUG-binding protein 2 (CUGbp2). These studies suggest that Fgf9 is an important factor in the regulation of Ptgs2 in colonic MSCs and may be a factor involved in its constitutive expression in vivo.
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ABSTRACT: The tumor microenvironment presents an exciting opportunity for innovative prognostic and therapeutic approaches to human cancer. The diverse cellular and extracellular contribution to tumor growth argues that prevention and cure of human cancers will result only from a multifaceted approach to cancer therapy. In this review we provide a foundation for considering the mesenchymal contribution to the tumor microenvironment. We address normal mesenchymal development, physiological interactions between the epithelium and stroma and the cellular hierarchy within these compartments. We focus on cancer-associated fibroblasts in gastrointestinal malignancy but our models have also been informed by other tumor systems. The review provides a framework for characterizing the overall biological contribution of the mesenchyme to human disease. Understanding the biological heterogeneity of specific mesenchymal cells in cancer will provide new opportunities for targeted cancer prevention and therapy.Pharmacology [?] Therapeutics 08/2012; 136(2):131-41. DOI:10.1016/j.pharmthera.2012.08.007 · 7.75 Impact Factor
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ABSTRACT: Stem cell therapy for intestinal diseases is an emerging area in clinical gastroenterology. We will review recent literature regarding mesenchymal stem cells, which have been utilized in preclinical models and are now headed for clinical trials in several gastrointestinal diseases including inflammatory bowel disease. Important studies over the last 2 years have made significant inroads into understanding the mechanisms of action of these cell types. The two major competing hypotheses are that mesenchymal stem cells home to areas of injury where they repair based on their stem cell activity or that mesenchymal stem cells act as a source of secreted factors that stimulate repair and inhibit inflammation. Mesenchymal stem cells show promise for therapy in a number of intestinal diseases. Further understanding of their mechanism of action should improve our ability to use them therapeutically.Current opinion in gastroenterology 03/2011; 27(2):119-24. DOI:10.1097/MOG.0b013e3283423f20 · 3.66 Impact Factor
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ABSTRACT: Research on mesenchymal stem cells (MSC) has evolved rapidly during the last decade prompted by their potential use for tissue repair and immunotherapy. Not only can MSC differentiate into cells of the mesodermal lineage, but they also exhibit immunomodulatory functions depending on their interaction with cells of both innate and adaptive immune systems. Most aspects of MSC biology remain to be elucidated. It is emerging even more clearly that these cells are not always a panacea. Only the knowledge of their physiological role and their interactions with other cells will allow us to use them as a therapeutic tool.Seminars in Immunopathology 04/2011; 33(6):593-602. DOI:10.1007/s00281-011-0267-7 · 6.48 Impact Factor