Type IV collagen alpha6 chain-derived noncollagenous domain 1 (alpha6(IV)NC1) inhibits angiogenesis and tumor growth.

Type IV collagen is a major component of vascular basement membranes. The noncollagenous (NC1) domains of several alpha-chains of type IV collagen reveal a capacity to inhibit angiogenesis and tumor growth. Here, we demonstrate that the NC1 domain of the alpha6 chain of type IV collagen (alpha6NC1) is an endogenous inhibitor of angiogenesis and tumor growth.

Beta1 integrin expression on endothelial cells is required for angiogenesis but not for vasculogenesis.

Integrins are a family of cell adhesion receptors that are involved in cell-matrix and cell-cell communications. They facilitate cell proliferation, migration, and survival. Using the Cre-Lox system, we deleted beta1 integrin on Tie2-positive (Tie2-cre beta1 Int (fl/fl)) vascular endothelial cells.

Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts.

Activated fibroblasts are associated with many different tumors. Myofibroblasts, activated fibroblasts, and perivascular mesenchymal cells such as pericytes play a role in cancer progression. Many studies suggest that myofibroblasts facilitate tumor growth and cancer progression.

Structure and function of basement membranes.

Basement membranes (BMs) are present in every tissue of the human body. All epithelium and endothelium is in direct association with BMs. BMs are a composite of several large glycoproteins and form an organized scaffold to provide structural support to the tissue and also offer functional input to modulate cellular function.

Endothelial-to-mesenchymal transition contributes to cardiac fibrosis.

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.

Type IV collagen-derived angiogenesis inhibitors.

The concept of anti-angiogenesis therapy was introduced by Judah Folkman in 1971 and since then, a plethora of pro- and anti-angiogenic factors have been identified. In the recent years, it has become clear that angiogenesis, the formation of new capillaries from a pre-existing capillary network, is highly regulated by the action of pro- and anti-angiogenic factors. In the healthy adult organism the "angiogenic-switch" is likely turned "Off", i.

Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition.

Activated fibroblasts are key contributors to the fibrotic extracellular matrix accumulation during liver fibrosis. The origin of such fibroblasts is still debated, although several studies point to stellate cells as the principal source. The role of adult hepatocytes as contributors to the accumulation of fibroblasts in the fibrotic liver is yet undetermined.

Near equivalence of human click-evoked and stimulus-frequency otoacoustic emissions.

Otoacoustic emissions (OAEs) evoked by broadband clicks and by single tones are widely regarded as originating via different mechanisms within the cochlea. Whereas the properties of stimulus-frequency OAEs (SFOAEs) evoked by tones are consistent with an origin via linear mechanisms involving coherent wave scattering by preexisting perturbations in the mechanics, OAEs evoked by broadband clicks (CEOAEs) have been suggested to originate via nonlinear interactions among the different frequency components of the stimulus (e.g.

Renal fibrosis and glomerulosclerosis in a new mouse model of diabetic nephropathy and its regression by bone morphogenic protein-7 and advanced glycation end product inhibitors.

Diabetic nephropathy is currently the most common cause of end-stage renal disease (ESRD) in the western world. A mouse model for diabetic nephropathy that encompasses the salient features of this disease in the kidney is not available. Here, we report that CD1 mice, in contrast to inbred C57BL/6 and 129Sv strains, develop ESRD associated with prominent tubulointerstitial nephritis and fibrosis within 3 months and die because of diabetic complications by 6-7 months after a single injection of streptozotocin.

Choosing a mouse model to study the molecular pathobiology of Alport glomerulonephritis.

Alport syndrome, caused by mutations that interfere with the normal assembly of the alpha3alpha4alpha5(IV) collagen network in the glomerular basement membrane (GBM), is the most common inherited glomerular disease leading to renal failure. A detailed knowledge of the underlying pathogenic mechanisms is necessary for developing new, more specific, and effective therapeutic strategies aimed at delaying the onset and slowing disease progression. Studies of several dog and mouse models of Alport syndrome have significantly enhanced our understanding of the disease mechanisms and provided systems for testing potential therapies.

Transcriptional regulation of epithelial-mesenchymal transition.

It has become increasingly obvious that the notion of a terminally differentiated cell is likely a simplified concept. Epithelial-mesenchymal transition (EMT), during which epithelial cells assume a mesenchymal phenotype, is a key event occurring during normal development and pathological processes. Multiple extracellular stimuli and transcriptional regulators can trigger EMT, but how such distinct signaling pathways orchestrate the complex cellular events that facilitate EMT is not well understood.

Glomerular expression of nephrin and synaptopodin, but not podocin, is decreased in kidney sections from women with preeclampsia.

Background: Preeclampsia is a pregnancy-specific disorder characterized by hypertension and proteinuria. In other disease states, proteinuria has been linked to altered expressions of podocyte foot-process proteins, but this has not been studied in women with preeclampsia. We sought to test the hypothesis that proteinuria in preeclampsia is associated with dysregulated expression of the podocyte cytoskeleton and/or tight junction proteins.

Mechanisms of metastasis: epithelial-to-mesenchymal transition and contribution of tumor microenvironment.

Every year about 500,000 people in the United States die as a result of cancer. Among them, 90% exhibit systemic disease with metastasis. Considering this high rate of incidence and mortality, it is critical to understand the mechanisms behind metastasis and identify new targets for therapy.

Alphav beta6 integrin regulates renal fibrosis and inflammation in Alport mouse.

The transforming growth factor (TGF)-beta-inducible integrin alpha v beta6 is preferentially expressed at sites of epithelial remodeling and has been shown to bind and activate latent precursor TGF-beta. Herein, we show that alpha v beta6 is overexpressed in human kidney epithelium in membranous glomerulonephritis, diabetes mellitus, IgA nephropathy, Goodpasture's syndrome, and Alport syndrome renal epithelium. To assess the potential regulatory role of alpha v beta6 in renal disease, we studied the effects of function-blocking alpha v beta6 monoclonal antibodies (mAbs) and genetic ablation of the beta6 subunit on kidney fibrosis in Col4A3-/- mice, a mouse model of Alport syndrome.

BMP-7 functions as a novel hormone to facilitate liver regeneration.

Bone morphogenic protein-7 (BMP-7) is a key protein involved in liver organogenesis and development. The physiological circulating concentration of BMP-7 is between 100 and 300 pg/ml. BMP-7 expression is absent in the liver, but the receptors for BMP-7 are present on adult hepatocytes.

Identification of fibroblast heterogeneity in the tumor microenvironment.

Tumors are unorganized organs that contain many different cell types. In the recent years, many studies have reported that primary tumors contain fibroblasts/myofibroblasts (carcinoma-associated fibroblasts), mesenchymal cells such as pericytes/mural cells and other vascular smooth muscle cells. Several different markers are used routinely to identify carcinoma-associated fibroblasts (CAFs) such as alpha-smooth muscle actin (alpha-SMA), vimentin, S100A4 protein/fibroblast specific protein-1 (FSP1) and type I collagen.

Alpha-actinin-4 is required for normal podocyte adhesion.

Mutations in the alpha-actinin-4 gene ACTN4 cause an autosomal dominant human kidney disease. Mice deficient in alpha-actinin-4 develop a recessive phenotype characterized by kidney failure, proteinuria, glomerulosclerosis, and retraction of glomerular podocyte foot processes. However, the mechanism by which alpha-actinin-4 deficiency leads to glomerular disease has not been defined.

Proteinuria with and without renal glomerular podocyte effacement.

Renal biopsies of patients with proteinuria and kidney disease most often are associated with podocyte foot process effacement. For several decades, nephrologists have wondered whether proteinuria is a result of podocyte foot process effacement or the cause of it. In the past few years, the author's laboratory has addressed this issue using different mouse models of proteinuria.

Structural basis for the functions of endogenous angiogenesis inhibitors.

Tipping the angiogenic balance between pro- and antiangiogenic stimuli to favor vasculature induction and enhanced angiogenesis is a key event in the growth and progression of tumors. Recently, we demonstrated that the genetic loss of normal physiological levels of individual endogenous inhibitors of angiogenesis leads to a change in the balance between proangiogenic stimulators and their inhibitors, thus favoring enhanced angiogensis and increased tumor growth. Therefore, these endogenous angiogenesis inhibitors provide a physiological threshold against the induction of angiogenesis.

Chronic bile duct injury associated with fibrotic matrix microenvironment provokes cholangiocarcinoma in p53-deficient mice.

Intrahepatic cholangiocarcinoma (CCA) is a lethal malignancy of the biliary epithelium associated with p53 mutations, bile duct injury, inflammation, and fibrosis. Here, to validate these processes in CCA, we developed a liver cirrhosis model driven by chronic intermittent toxin exposure, which provokes bile duct injury/necrosis and proliferation, fibroblast recruitment, and progressive extracellular matrix (ECM) changes. Fibrotic changes in the matrix microenvironment, typified by increased type I and III collagens and fibroblast recruitment, were shown to stimulate biliary epithelium hyperplasia with subsequent progression to malignant intrahepatic CCA only in mice harboring a p53 mutant allele.

Bone-marrow-derived stem cells repair basement membrane collagen defects and reverse genetic kidney disease.

Type IV collagen is a predominant component of basement membranes, and glomeruli of a kidney filter approximately 70-90 liters of plasma every day through a specialized glomerular basement membrane (GBM). In Alport syndrome, a progressive disease primarily affecting kidneys, mutations in GBM-associated type IV collagen genes (COL4A3, COL4A4, or COL4A5) lead to basement membrane structural defects, proteinuria, renal failure, and an absence of all three GBM collagen triple helical chains because of obligatory posttranslational assembly requirements. Here, we demonstrate that transplantation of wild-type bone marrow (BM) into irradiated COL4A3(-/-) mice results in a possible recruitment of BM-derived progenitor cells as epithelial cells (podocytes) and mesangial cells within the damaged glomerulus, leading to a partial restoration of expression of the type IV collagen alpha3 chain with concomitant emergence of alpha4 and alpha5 chain expression, improved glomerular architecture associated with a significant reduction in proteinuria, and improvement in overall kidney histology compared with untreated COL4A3(-/-) mice or irradiated COL4A3(-/-) mice with BM from adult COL4A3(-/-) mice.

Fibroblasts in cancer.

Tumours are known as wounds that do not heal - this implies that cells that are involved in angiogenesis and the response to injury, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression, and their structural and functional contributions to this process are beginning to emerge. Their production of growth factors, chemokines and extracellular matrix facilitates the angiogenic recruitment of endothelial cells and pericytes.

The epithelial-mesenchymal transition: new insights in signaling, development, and disease.

The conversion of an epithelial cell to a mesenchymal cell is critical to metazoan embryogenesis and a defining structural feature of organ development. Current interest in this process, which is described as an epithelial-mesenchymal transition (EMT), stems from its developmental importance and its involvement in several adult pathologies. Interest and research in EMT are currently at a high level, as seen by the attendance at the recent EMT meeting in Vancouver, Canada (October 1-3, 2005).