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.
"Gene expression profiling data used for analyses were obtained from the Gene Expression Omnibus (GEO) database as follows. GSE30056 associated with Hayashi et al.  for EpiSCs and EpiLCs; GSE14012 associated with Sridharan et al.  for MEFs, iPSCs, and piPSCs; GSE34799 associated with Rugg-Gunn et al.  for ESCs and EpiSCs; GSE21222 associated with Hanna et al.  for human iPSCs in naïve and primed states; GSE11274 associated with Ko et al.  for germline stem cells (GSCs), germline-derived pluripotent stem cells (gPSCs), and neural stem cell (NSC)s; GSE31028 associated with Lien et al.  for quiescent and activated hair follicular stem cell (HFSC)s; GSE6506 associated with Chambers et al.  for long-term hematopoietic stem cell (LT-HSC)s, granulocytes, and B cells; GSE9954 associated with Thorrez et al.  for ovary, testis, bone marrow, placenta, adipose tissue, kidney, liver, pancreas, lung, brain, and heart; GSE19233 associated with Walker et al.  for bone marrow mesenchymal stem cell (MSC)s; GSE31150 associated with Pardo et al.  for pancreas. Microarray expression data were background subtracted and normalized by the robust multi-array analysis method  using R-package 2.8.1 with Bioconductor 2.6 . "
[Show abstract][Hide abstract] ABSTRACT: Predominant transcriptional subnetworks called Core, Myc, and PRC modules have been shown to participate in preservation of the pluripotency and self-renewality of embryonic stem cells (ESCs). Epiblast stem cells (EpiSCs) are another cell type that possesses pluripotency and self-renewality. However, the roles of these modules in EpiSCs have not been systematically examined to date. Here, we compared the average expression levels of Core, Myc, and PRC module genes between ESCs and EpiSCs. EpiSCs showed substantially higher and lower expression levels of PRC and Core module genes, respectively, compared with those in ESCs, while Myc module members showed almost equivalent levels of average gene expression. Subsequent analyses revealed that the similarity in gene expression levels of the Myc module between these two cell types was not just overall, but striking similarities were evident even when comparing the expression of individual genes. We also observed equivalent levels of similarity in the expression of individual Myc module genes between induced pluripotent stem cells (iPSCs) and partial iPSCs that are an unwanted byproduct generated during iPSC induction. Moreover, our data demonstrate that partial iPSCs depend on a high level of c-Myc expression for their self-renewal properties.
PLoS ONE 12/2013; 8(12):e83769. DOI:10.1371/journal.pone.0083769 · 3.23 Impact Factor
"It is unclear whether the pericryptal fibroblasts, the αSMA+ fibroblasts, the muscularis mucosae and αSMA negative fibroblasts have a common origin, or if these different cells reflect differing stages within a unified mesenchymal hierarchy, represent lineage diversity from a common origin, or are truly distinct lineages both biologically and developmentally (Fig. 3). A series of elegant studies has revealed that true MSCs may be isolated from the gastrointestinal tract (Brown et al., 2007; Walker et al., 2010; Manieri et al., 2012). This suggests that a mesenchymal hierarchy does indeed exist, although the exact location and function of gastrointestinal MSCs in health and cancer remain to be fully elucidated (Brown et al., 2007; Powell & Saada, 2012). "
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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 · 4.29 Impact Factor
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