In this case, COX-2 expression is also serving an antifibrotic role via elaboration of prostanoids, which are known to inhibit collagen production as well as fibroblast proliferation (6). Differentiation of fibroblasts into α-smooth muscle actin (SMA)–expressing myofibroblasts represents a critical step in the pathogenesis of fibrotic disorders, and is … We conclude that Ang II mediates the fibroblast-myofibroblast transition partially via the Ang II/CaMKII/TGF-β1/Cx43 signaling pathway. Interestingly, the myofibroblast phenotype is associated with absence of Thy-1 expression (4), similar to that observed for the telomerase as well as caveolin-1– expressing fibroblast phenotypes (7, 8). Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. These p38-mediated mechanisms promoting myofibroblast differentiation may be the basis for the ability of p38 inhibitors to suppress pulmonary fibrosis in animal model studies (39). Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis. The Thy-1–expressing fibroblast has more recently been reported to have less fibrogenic properties than its Thy-1–negative counterpart (3). It can contract by using some of the cytoskeletal proteins that are normally found in smooth muscle cells, in particular a form of actin called alpha-smooth muscle actin. Overactive myofibroblasts, by contrast, are involved in abnormal scarring. Lama VN, Smith L, Badri L, Flint A, Andrei AC, Murray S, Wang Z, Liao H, Toews GB, Krebsbach PH. Mechanical stretch modulates the promoter activity of the profibrotic factor CCN2 through increased actin polymerization and NF-kappaB activation. Evidence that fibroblasts derive from epithelium during tissue fibrosis. Furukawa F, Matsuzaki K, Mori S, Tahashi Y, Yoshida K, Sugano Y, Yamagata H, Matsushita M, Seki T, Inagaki Y. Deaton RA, Su C, Valencia TG, Grant SR. Thy-1− and caveolin-1− fibroblasts are also associated with fibrotic lungs, and these two markers are lacking in myofibroblasts (3, 8), thus indicating some role in fibrosis. Yokota T, Kawakami Y, Nagai Y, Ma JX, Tsai JY, Kincade PW, Sato S. Bone marrow lacks a transplantable progenitor for smooth muscle type alpha-actin-expressing cells. Fibroblasts differentiate into myofibroblast due to mechanical stress and soluble chemical factors like TGF-β1. It is also unclear if some of the differentiated phenotypes, such as deficient COX-2 expression, are in any way related to the distinct myofibroblasts, which are present in virtually all fibrotic lesions. Regulation of telomerase activity in lung fibroblasts. This antifibrotic role of caveolin-1 is confirmed by evidence that overexpression of this molecule suppresses myofibroblast differentiation and bleomycin-induced pulmonary fibrosis, whereas deficiency in its expression results in pulmonary fibrosis. Fibrotic lesions, including those present as “fibroblastic foci” in usual interstitial pneumonia or idiopathic pulmonary fibrosis (IPF), are highlighted by the presence of fibroblasts, or cells with morphologic characteristics of fibroblasts (1). Collectively, miR-125b has a concomitant effect on other important cellular processes including epistatic regulation of proliferation and TGF-β pathways, thereby promoting cardiac fibrosis. Hu B, Wu Z, Phan SH. Given that the fibrocytes can only elaborate less than 10% of the level of collagen production in tissue-derived fibroblasts, it has been suggested that the fibrocyte may play an indirect role by secretion of fibrogenic mediators, such as TGF-β, to promote myofibroblast differentiation in locally derived tissue fibroblasts (25). Beyond these common characteristics, it is unclear if these are manifestations of the same cell, or of different cell subpopulations whose interrelationships, if any, remain unclear. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Differentiating fibroblasts acquire a highly secretory myofibroblast phenotype characterized by αSMA expression, which correlates with increased secretion of profibrotic extracellular matrix components like collagen and fibronectin. Interestingly, the myofibroblast phenotype is associated with absence of Thy-1 expression , similar to that observed for the telomerase as well as caveolin-1– expressing fibroblast phenotypes (7, 8). Indeed, p38 kinase activation induced by mechanical stress on the cell requires the presence of α-smooth muscle actin, and the interaction between these two components facilitates access to p38 substrates (36). Consistent with this finding is the presence of fibroblasts derived from circulating fibrocytes in animal model studies (21–23). Many myofibroblast precursors are mesenchymal and locally available, including fibroblasts and mesenchymal progenitor cells that reside in the connective tissue architecture of all organs. 5. Conversely, reduced caveolin-1 expression is reported in IPF lung tissue and fibroblasts relative to that in normal lungs. Schematic illustration showing the evolution of the (myo)fibroblast phenotype. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie X, Vulto I, Phillips JA III. Frid MG, Kale VA, Stenmark KR. But it is unclear if these different phenotypes are characteristics of distinct subpopulations with unique progenitors or represent the different stages of differentiation from a common progenitor. An essential role for CCAAT/enhancer binding protein beta in bleomycin-induced pulmonary fibrosis. Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP. Fibrocytes from burn patients regulate the activities of fibroblasts. Results: Restenotic plaques demonstrated increased stellate cells (2.7 ± 0.15 vs.1.3 ± 0.15) fibroblasts (2282.2 ± 85.9 vs. 906.4 ± 134.5) and myofibroblasts (18.5 ± 1.2 vs.10.6 ± 1.0) p = 0.0001 for all comparisons. The function of fibroblasts in fibrosis has been viewed primarily in the narrow context of their ability to elaborate extracellular matrix, and perhaps in elaboration of cytokines and regulation of tissue mechanical properties. Consistent with such a role is the observation that caveolin-1 deficiency is associated with the development of lung fibrotic lesions, whereas its induced overexpression affords some protection against fibrosis (8). Hashimoto S, Gon Y, Takeshita I, Matsumoto K, Maruoka S, Horie T. Transforming growth factor-β1 induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. The myofibroblast (a fibroblast with α-smooth muscle actin among other contractile elements) has been identified as a key mediator of idiopathic pulmonary fibrosis (IPF) and other profibrotic conditions –. Wang J, Fan J, Laschinger C, Arora PD, Kapus A, Seth A, McCulloch CA. Correspondence and requests for reprints should be addressed to Dr. Sem H. Phan, M.D., Ph.D., Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200. It appears, therefore, that the active fibrotic phenotype embodied in the myofibroblast may be the result of a differentiation mechanism that inactivates normally or homeostatically inhibitory pathways. Their origins, potential interrelationships, interactions, and the mechanisms that gave rise to these phenotypes have been characterized to a limited extent in a compartmentalized manner that prevents full appreciation of their precise roles in the overall pathogenesis of progressive fibrotic lung diseases. Biology of Fibroblasts and Myofibroblasts. Systemic Sclerosis (SSc) is characterized by dysregulated fibroblast to myofibroblast differentiation and excessive extracellular matrix deposition, resulting in skin fibrosis. https://doi.org/10.1016/j.ejphar.2014.04.007. In addition to the secretion of the ECM, (myo)fibroblasts, by … Phan SH. A key cell in the pathophysiology of SSc is the myofibroblast. Our objective was to … For the purposes of this conference, the two functions in the adult lung—namely, lung repair/fibrosis and regeneration—provide the compelling rationale for detailed studies on the origin of these cells, their phenotypic and functional characteristics, and their fate in the context of resolution versus progressive fibrosis. (A) qRT‐PCR assay of miR‐503 levels in fibroblasts treated with different doses of TGF‐β1 for 48 h, with *P < .05 and **P < .01 vs the dose 0 group. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, Belperio JA, Keane MP, Strieter RM. Zhang A, Liu X, Cogan JG, Fuerst MD, Polikandriotis JA, Kelm RJ Jr, Strauch AR. Thus, most of the studies focused on aspects of TGF-β signaling that gives rise to the differentiated phenotype, with primary focus on the expression of the marker gene, α-smooth muscle actin. It is unclear at this time whether these different phenotypes represent various stages of differentiation that may ultimately lead to the myofibroblast or, alternatively, represent independent subpopulations arising from distinct progenitors. Although some studies using certain fibrocyte markers (CD34, CD45, collagen I) and, in some cases, CXCR4 expression suggest that the fibrocytes represent a significant source of myofibroblasts in the lung undergoing fibrosis (22, 23), other studies cannot demonstrate the ability of bone marrow–derived fibroblast-like cells to differentiate to myofibroblasts (18–20, 24). Has highlighted the complexity of the gastrointestinal and genitourinary tracts, Borok Z previous research showed that the up-regulation miR-503... Is suggested by evidence that epigenetic regulation may also be important had more latent active. It has long been considered that fibrosis and is not intended to be a comprehensive review αSMA in. Mediators and TGFβ-induced signaling pathways: clinical relevance of pathologic classification myo ) fibroblasts are key players for maintaining homeostasis. Systemic myofibroblast vs fibroblast ( SSc ) is a form of fibroblast cell that has partially... 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