1: Development. 2008 Nov;135(21):3611-22. Epub 2008 Oct 2. Links
Frs2{alpha}-deficiency in cardiac progenitors disrupts a subset of FGF signals required for outflow tract morphogenesis.
Zhang J, Lin Y, Zhang Ymodulate, Lan Y, Lin C, Moon AM, Schwartz RJ, Martin JF, Wang F.
Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Boulevard, Houston, TX 77030, USA.
The cardiac outflow tract (OFT) is a developmentally complex structure derived from multiple lineages and is often defective in human congenital anomalies. Although emerging evidence shows that fibroblast growth factor (FGF) is essential for OFT development, the downstream pathways mediating FGF signaling in cardiac progenitors remain poorly understood. Here, we report that FRS2alpha (FRS2), an adaptor protein that links FGF receptor kinases to multiple signaling pathways, mediates crucial aspects of FGF-dependent OFT development in mouse. Ablation of Frs2alpha in mesodermal OFT progenit
or cells that originate in the second heart field (SHF) affects their expansion into the OFT myocardium, resulting in OFT misalignment and hypoplasia. Moreover, Frs2alpha mutants have defective endothelial-to-mesenchymal transition and neural crest cell recruitment into the OFT cushions, resulting in OFT septation defects. These results provide new insight into the signaling molecules downstream of FGF receptor tyrosine kinases in cardiac progenitors.
PMID: 18832393 [PubMed - in process]
1: J Cell Biol. 2008 Jul 28;182(2):315-25. Links
Slug is a direct Notch target required for initiation of cardiac cushion cellularization.
Niessen K, Fu Y, Chang L, Hoodless PA, McFadden D, Karsan A.
Department of Medical Biophysics, British Columbia Cancer Agency, Vancouver V5Z 1L3, Canada.
Snail family proteins are key regulators of epithelial-mesenchymal transition, but their role in endothelial-to-mesenchymal transition (EMT) is less well studied. We show that Slug, a Snail family member, is expressed by a subset of endothelial cells as well as mesenchymal cells of the atrioventricular canal and outflow tract during cardiac cushion morphogenesis. Slug deficiency results in impaired cellularization of the cardiac cushion at embryonic day (E)-9.5 but is compensated by increased Snail expression at E10.5, which restores cardiac cushion EMT. We further demonstrate that Slug, but not Snail, is directly up-regulated by Notch in endothelial cells and that Slug expression is required for Notch-mediated repression of the vascular endothelial cadherin promoter and for promoting migration of transformed endothelial cells. In contrast, transforming growth factor beta (TGF-beta) induces Snail but not Slug. Interestingly, activation of Notch in the context of TGF-beta stimulation results in synergistic up-regulation of Snail in endothelial cells. Collectively, our data suggest that combined expression of Slug and Snail is required for EMT in cardiac cushion morphogenesis.
PMID: 18663143 [PubMed - indexed for MEDLINE]
PMCID: PMC2483533 [Available on 01/28/09]
The role of endothelial-to-mesenchymal transition in cancer progression.
Potenta S, Zeisberg E, Kalluri R.
[1] 1Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA [2] 2Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Recent evidence has demonstrated that endothelial-to-mesenchymal transition (EndMT) may have a significant role in a number of diseases. Although EndMT has been previously studied as a critical process in heart development, it is now clear that EndMT can also occur postnatally in various pathologic settings, including cancer and cardiac fibrosis. During EndMT, resident endothelial cells delaminate from an organised cell layer and acquire a mesenchymal phenotype characterised by loss of cell-cell junctions, loss of endothelial markers, gain of mesenchymal markers, and acquisition of invasive and migra
tory properties. Endothelial-to-mesenchymal transition -derived cells are believed to function as fibroblasts in damaged tissue, and may therefore have an important role in tissue remodelling and fibrosis. In tumours, EndMT is an important source of cancer-associated fibroblasts (CAFs), which are known to facilitate tumour progression in several ways. These new findings suggest that targeting EndMT may be a novel therapeutic strategy, which is broadly applicable not only to cancer but also to various other disease states.British Journal of Cancer advance online publication, 16 September 2008; doi:10.1038/sj.bjc.6604662 www.bjcancer.
PMID: 18797460 [PubMed - as supplied by publisher]
1: Curr Opin Gastroenterol. 2008 Jul;24(4):462-8. Links
Intestinal fibrosis in inflammatory bowel disease: progress in basic and clinical science.
Rieder F, Fiocchi C.
Department of Internal Medicine I, University of Regensburg, Regensburg, Germany.
PURPOSE OF REVIEW: Intestinal fibrosis is a potentially serious complication of inflammatory bowel disease and its pathophysiology is still unclear. This review will discuss recent developments relating to sources of fibroblasts in intestinal inflammation, mediators that modulate fibroblast activation and function, as well as new clinical, laboratory, endoscopic and radiological studies aimed at improving diagnosis and management of intestinal fibrosis in inflammatory bowel disease. RECENT FINDINGS: The fibroblast remains the central cell responsible for intestinal fibrosis in inflammatory bowel disease and transforming growth factor-beta1 is still the most potent pro-fibrogenic cytokine. Novel mediators, however, are being identified that modulate fibroblast function, such as interleukin-13, interleukin-21, galectin-3, osteopontin, Wnt and toll-like receptor ligands, and anti-tumor necrosis factor-alpha agents. New fibroblast sources are being identified, such as fibrocytes, and new mechanisms of fibroblast generation, like epithelial- and endothelial-to-mesenchymal transition. Animal models of intestinal fibrosis are still few, but new ways to induce gut fibrosis are being explored. Serological markers indicating a clinically complicated course that includes intestinal fibrosis are promising an
d are being tested in adult and pediatric populations, particularly in Crohn's disease. Video capsule endoscopy, the Given Patency capsule, double balloon enteroscopy, and computed tomographic enteroscopy are some of the new modalities being developed to assess the risk and improve the diagnosis of intestinal fibrosis. Novel therapeutic approaches include endoscopic balloon dilatation with conventional and double balloon enteroscopy, and local injection of glucocorticoids and tumor necrosis factor-alpha blockers, showing partial but encouraging success. SUMMARY: More studies are needed to improve knowledge of the pathophysiology of intestinal fibrosis if better preventive, diagnostic and therapeutic measures are to be expected in the near future.
PMID: 18622160 [PubMed - indexed for MEDLINE]
Nat Med. 2007 Aug;13(8):952-61. Epub 2007 Jul 29. Links
Endothelial-to-mesenchymal transition contributes to cardiac fibrosis.
Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandr
aker A, Yuan X, Pu WT, Roberts AB, Neilson EG, Sayegh MH, Izumo S, Kalluri R.
Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, Massachusetts 02215, USA.
Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-beta1 (TGF-beta1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse
models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.

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