http://www.fibrogenesis.com The most accessed research articles published by Fibrogenesis & Tissue Repair 2012-05-07T00:00:00Z Background: Peroxisome proliferator-activated receptor (PPAR)γ may be a key regulator of connective tissue deposition and remodeling in vivo. PPARγ expression is reduced in dermal fibroblasts isolated from fibrotic areas of scleroderma patients; PPARγ agonists suppress the persistent fibrotic phenotype of this cell type. Previously, we showed that loss of PPARγ expression in fibroblasts resulted in enhanced bleomycin-induced skin fibrosis. However, whether loss of PPARγ expression in skin fibroblasts affects cutaneous tissue repair or homeostasis is unknown. Results: Mice deleted for PPARγ in skin fibroblasts show an enhanced rate of dermal wound closure, concomitant with elevated phosphorylation of Smad3, Akt and ERK, and increased expression of proliferating cell nuclear antigen (PCNA), collagen, α-smooth muscle actin (α-SMA) and CCN2. Conversely, dermal homeostasis was not appreciably affected by loss of PPARγ expression. Conclusion: PPARγ expression by fibroblasts suppresses cutaneous tissue repair. In the future, direct PPARγ antagonists and agonists might be of clinical benefit in controlling chronic wounds or scarring, respectively. http://www.fibrogenesis.com/content/5/1/5 Wei Sha Katherine Thompson Jennifer South Murray Baron Andrew Leask Fibrogenesis & Tissue Repair 2012, null:5 2012-04-13T00:00:00Z doi:10.1186/1755-1536-5-5 /content/figures/1755-1536-5-5-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 5 2012-04-13T00:00:00Z XML Heat shock protein 27 (HSP27) is a multidimensional protein which acts as a protein chaperone and an antioxidant and plays a role in the inhibition of apoptosis and actin cytoskeletal remodeling. In each of these capacities, HSP27 has been implicated in different disease states playing both protective and counter-protective roles. The current review presents HSP27 in multiple disease contexts: renal injury and fibrosis, cancer, neuro-degenerative and cardiovascular disease, highlighting its role as a potential biomarker and therapeutic target. http://www.fibrogenesis.com/content/5/1/7 Aparna Vidyasagar Nancy Wilson Arjang Djamali Fibrogenesis & Tissue Repair 2012, null:7 2012-05-07T00:00:00Z doi:10.1186/1755-1536-5-7 /content/figures/1755-1536-5-7-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 7 2012-05-07T00:00:00Z PDF Reactive oxygen species (ROS) generated within cells or, more generally, in a tissue environment, may easily turn into a source of cell and tissue injury. Aerobic organisms have developed evolutionarily conserved mechanisms and strategies to carefully control the generation of ROS and other oxidative stress-related radical or non-radical reactive intermediates (that is, to maintain redox homeostasis), as well as to 'make use' of these molecules under physiological conditions as tools to modulate signal transduction, gene expression and cellular functional responses (that is, redox signalling). However, a derangement in redox homeostasis, resulting in sustained levels of oxidative stress and related mediators, can play a significant role in the pathogenesis of major human diseases characterized by chronic inflammation, chronic activation of wound healing and tissue fibrogenesis. This review has been designed to first offer a critical introduction to current knowledge in the field of redox research in order to introduce readers to the complexity of redox signalling and redox homeostasis. This will include ready-to-use key information and concepts on ROS, free radicals and oxidative stress-related reactive intermediates and reactions, sources of ROS in mammalian cells and tissues, antioxidant defences, redox sensors and, more generally, the major principles of redox signalling and redox-dependent transcriptional regulation of mammalian cells. This information will serve as a basis of knowledge to introduce the role of ROS and other oxidative stress-related intermediates in contributing to essential events, such as the induction of cell death, the perpetuation of chronic inflammatory responses, fibrogenesis and much more, with a major focus on hepatic chronic wound healing and liver fibrogenesis. http://www.fibrogenesis.com/content/1/1/5 Erica Novo Maurizio Parola Fibrogenesis & Tissue Repair 2008, null:5 2008-10-13T00:00:00Z doi:10.1186/1755-1536-1-5 /content/figures/1755-1536-1-5-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 5 2008-10-13T00:00:00Z XML Background: Transforming growth factor-beta1 (TGF-beta1) is a potent regulator of cell growth and differentiation. TGF-beta1 has been shown to be a key player in tissue remodeling processes in a number of disease states by inducing expression of extracellular matrix proteins. In this study a quantitative proteomic analysis was undertaken to investigate if TGF-beta1 contributes to tissue remodeling by mediating mRNA splicing and production of alternative isoforms of proteins.Methodology/Principal findingsThe expression of proteins involved in mRNA splicing from TGF-beta1-stimulated lung fibroblasts was compared to non-stimulated cells by employing isotope coded affinity tag (ICATTM) reagent labeling and tandem mass spectrometry. A total of 1733 proteins were identified and quantified with a relative standard deviation of 11% +/ 8 from enriched nuclear fractions. Seventy-six of these proteins were associated with mRNA splicing, including 22 proteins involved in splice site selection. In addition, TGF-beta1 was observed to alter the relative expression of splicing proteins that may be important for alternative splicing of fibronectin. Specifically, TGF-beta1 significantly induced expression of SRp20, and reducedthe expression of SRp30C, which has been suggested to be a prerequisite for generation of alternatively spliced fibronectin. The induction of SRp20 was further confirmed by westernblot and immunofluorescence. Conclusions: The results show that TGF-beta1 induces the expression of proteins involved in mRNA splicing and RNA processing in human lung fibroblasts. This may have an impact on the production of alternative isoforms of matrix proteins and can therefore be an important factor in tissue remodeling and disease progression. http://www.fibrogenesis.com/content/5/1/6 Oskar Hallgren Johan Malmström Lars Malmström Annika Andersson-Sjöland Marie Wildt Ellen Tufvesson Peer Juhasz Gyorgy Marko-Varga Gunilla Westergren-Thorsson Fibrogenesis & Tissue Repair 2012, null:6 2012-04-28T00:00:00Z doi:10.1186/1755-1536-5-6 /content/figures/1755-1536-5-6-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 6 2012-04-28T00:00:00Z PDF In the last decade there have been multiple studies concerning the contribution of endothelial progenitor cells (EPCs) to new vessel formation in different physiological and pathological settings. The process by which EPCs contribute to new vessel formation in adults is termed postnatal vasculogenesis and occurs via four inter-related steps. They must respond to chemoattractant signals and mobilize from the bone marrow to the peripheral blood; home in on sites of new vessel formation; invade and migrate at the same sites; and differentiate into mature endothelial cells (ECs) and/or regulate pre-existing ECs via paracrine or juxtacrine signals. During these four steps, EPCs interact with different physiological compartments, namely bone marrow, peripheral blood, blood vessels and homing tissues. The success of each step depends on the ability of EPCs to interact, adapt and respond to multiple molecular cues. The present review summarizes the interactions between integrins expressed by EPCs and their ligands: extracellular matrix components and cell surface proteins present at sites of postnatal vasculogenesis. The data summarized here indicate that integrins represent a major molecular determinant of EPC function, with different integrin subunits regulating different steps of EPC biology. Specifically, integrin α4β1 is a key regulator of EPC retention and/or mobilization from the bone marrow, while integrins α5β1, α6β1, αvβ3 and αvβ5 are major determinants of EPC homing, invasion, differentiation and paracrine factor production. β2 integrins are the major regulators of EPC transendothelial migration. The relevance of integrins in EPC biology is also demonstrated by many studies that use extracellular matrix-based scaffolds as a clinical tool to improve the vasculogenic functions of EPCs. We propose that targeted and tissue-specific manipulation of EPC integrin-mediated interactions may be crucial to further improve the usage of this cell population as a relevant clinical agent. http://www.fibrogenesis.com/content/5/1/4 Francisco Caiado Sergio Dias Fibrogenesis & Tissue Repair 2012, null:4 2012-03-12T00:00:00Z doi:10.1186/1755-1536-5-4 /content/figures/1755-1536-5-4-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 4 2012-03-12T00:00:00Z XML Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors (PRR) that play a key role in innate and adaptive immunity by recognizing structural components unique to bacteria, fungi and viruses. TLR4 is the most studied of the TLRs, and its primary exogenous ligand is lipopolysaccharide, a component of Gram-negative bacterial walls. In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling. In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis. In liver, TLR4 is expressed by all parenchymal and non-parenchymal cell types, and contributes to tissue damage caused by a variety of etiologies. Intact TLR4 signaling was identified in hepatic stellate cells (HSCs), the major fibrogenic cell type in injured liver, and mediates key responses including an inflammatory phenotype, fibrogenesis and anti-apoptotic properties. Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies. http://www.fibrogenesis.com/content/3/1/21 Jinsheng Guo Scott Friedman Fibrogenesis & Tissue Repair 2010, null:21 2010-10-21T00:00:00Z doi:10.1186/1755-1536-3-21 /content/figures/1755-1536-3-21-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 21 2010-10-21T00:00:00Z XML Fibrosis represents a major global disease burden, yet a potent antifibrotic compound is still not in sight. Part of the explanation for this situation is the difficulties that both academic laboratories and research and development departments in the pharmaceutical industry have been facing in re-enacting the fibrotic process in vitro for screening procedures prior to animal testing. Effective in vitro characterization of antifibrotic compounds has been hampered by cell culture settings that are lacking crucial cofactors or are not holistic representations of the biosynthetic and depositional pathway leading to the formation of an insoluble pericellular collagen matrix. In order to appreciate the task which in vitro screening of antifibrotics is up against, we will first review the fibrotic process by categorizing it into events that are upstream of collagen biosynthesis and the actual biosynthetic and depositional cascade of collagen I. We point out oversights such as the omission of vitamin C, a vital cofactor for the production of stable procollagen molecules, as well as the little known in vitro tardy procollagen processing by collagen C-proteinase/BMP-1, another reason for minimal collagen deposition in cell culture. We review current methods of cell culture and collagen quantitation vis-à-vis the high content options and requirements for normalization against cell number for meaningful data retrieval. Only when collagen has formed a fibrillar matrix that becomes cross-linked, invested with ligands, and can be remodelled and resorbed, the complete picture of fibrogenesis can be reflected in vitro. We show here how this can be achieved. A well thought-out in vitro fibrogenesis system represents the missing link between brute force chemical library screens and rational animal experimentation, thus providing both cost-effectiveness and streamlined procedures towards the development of better antifibrotic drugs. http://www.fibrogenesis.com/content/2/1/7 Clarice Chen Michael Raghunath Fibrogenesis & Tissue Repair 2009, null:7 2009-12-15T00:00:00Z doi:10.1186/1755-1536-2-7 /content/figures/1755-1536-2-7-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 7 2009-12-15T00:00:00Z XML Obstructive cholestasis causes hepatic cirrhosis and portal hypertension. The pathophysiological mechanisms involved in the development of liver disease are multiple and linked. We propose grouping these mechanisms according to the three phenotypes mainly expressed in the interstitial space in order to integrate them.Experimental extrahepatic cholestasis is the model most frequently used to study obstructive cholestasis. The early liver interstitial alterations described in these experimental models would produce an ischemia/reperfusion phenotype with oxidative and nitrosative stress. Then, the hyperexpression of a leukocytic phenotype, in which Kupffer cells and neutrophils participate, would induce enzymatic stress. And finally, an angiogenic phenotype, responsible for peribiliary plexus development with sinusoidal arterialization, occurs. In addition, an intense cholangiocyte proliferation, which acquires neuroendocrine abilities, stands out. This histopathological finding is also associated with fibrosis.It is proposed that the sequence of these inflammatory phenotypes, perhaps with a trophic meaning, ultimately produces a benign tumoral biliary process – although it poses severe hepatocytic insufficiency. Moreover, the persistence of this benign tumor disease would induce a higher degree of dedifferentiation and autonomy and, therefore, its malign degeneration. http://www.fibrogenesis.com/content/1/1/6 Maria-Angeles Aller Jorge-Luis Arias Jose Garcia-Dominguez Jose-Ignacio Arias Manuel Duran Jaime Arias Fibrogenesis & Tissue Repair 2008, null:6 2008-11-03T00:00:00Z doi:10.1186/1755-1536-1-6 /content/figures/1755-1536-1-6-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 6 2008-11-03T00:00:00Z XML There is currently much interest in adult mesenchymal stem cells (MSCs) and their ability to differentiate into other cell types, and to partake in the anatomy and physiology of remote organs. It is now clear these cells may be purified from several organs in the body besides bone marrow. MSCs take part in wound healing by contributing to myofibroblast and possibly fibroblast populations, and may be involved in epithelial tissue regeneration in certain organs, although this remains more controversial. In this review, we examine the ability of MSCs to modulate liver, kidney, heart and intestinal repair, and we update their opposing qualities of being less immunogenic and therefore tolerated in a transplant situation, yet being able to contribute to xenograft models of human tumour formation in other contexts. However, such observations have not been replicated in the clinic. Recent studies showing the clinical safety of MSC in several pathologies are discussed. The possible opposing powers of MSC need careful understanding and control if their clinical potential is to be realised with long-term safety for patients. http://www.fibrogenesis.com/content/4/1/20 William Otto Nicholas Wright Fibrogenesis & Tissue Repair 2011, null:20 2011-09-08T00:00:00Z doi:10.1186/1755-1536-4-20 /content/figures/1755-1536-4-20-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 20 2011-09-08T00:00:00Z XML In most adult epithelia the process of replacing damaged or dead cells is maintained through the presence of stem/progenitor cells, which allow epithelial tissues to be repaired following injury. Existing evidence strongly supports the presence of stem cells in the adult kidney. Indeed, recent findings provide evidence in favour of a role for intrinsic renal cells and against a physiological role for bone marrow-derived stem cells in the regeneration of renal epithelial cells. In addition, recent studies have identified a subset of CD24+CD133+ renal progenitors within the Bowman's capsule of adult human kidney, which provides regenerative potential for injured renal epithelial cells. Intriguingly, CD24+CD133+ renal progenitors also represent common progenitors of tubular cells and podocytes during renal development. Chronic injury causes dysfunction of the tubular epithelial cells, which triggers the release of fibrogenic cytokines and recruitment of inflammatory cells to injured kidneys. The rapid interposition of scar tissue probably confers a survival advantage by preventing infectious microorganisms from invading the wound, but prevents subsequent tissue regeneration. However, the existence of renal epithelial progenitors in the kidney suggests a possible explanation for the regression of renal lesions which has been observed in experimental animals and even in humans. Thus, manipulation of the wound repair process in order to shift it towards regeneration will probably require the ability to slow the rapid fibrotic response so that renal progenitor cells can allow tissue regeneration rather than scar formation. http://www.fibrogenesis.com/content/2/1/3 Paola Romagnani Raghu Kalluri Fibrogenesis & Tissue Repair 2009, null:3 2009-06-26T00:00:00Z doi:10.1186/1755-1536-2-3 /content/figures/1755-1536-2-3-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 3 2009-06-26T00:00:00Z XML