Notch3 Regulates Cardiac Fibroblast Proliferation, Apoptosis, and Fibroblast to Myofibroblast Transition via the RhoA/ROCK/Hif1α Pathway. 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. Int Rev Cytol. Differential collagen and fibronectin production by Thy 1+ and Thy 1− lung fibroblast subpopulations. Future studies into these areas are necessary to shed more light on their feasibility as targets for controlling fibrosis. The myofibroblast embodies the key features of active fibrosis by its ability to express high levels of extracellular matrix and fibrogenic cytokines, and to contribute to the altered mechanical properties of affected tissues. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. Reversal of myofibroblast differentiation: A review, S-Nitroso-N-acetylcysteine (PubChem CID: 10313479). The fact that fibrosis may be due to loss of antifibrotic properties rather than activation of fibrotic processes suggests that, in normal tissues, active mechanisms to suppress fibrosis may be constitutively important in maintaining tissue homeostasis. (Myo)fibroblasts are key players for maintaining skin homeostasis and for orchestrating physiological tissue repair. More recently, similar suppression of α-smooth muscle actin expression inhibits connective tissue growth factor (CTGF) promoter activity, which is associated with reduced nuclear factor (NF)-κB nuclear translocation (34). Hu B, Ullenbruch MR, Jin H, Gharaee-Kermani M, Phan SH. Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis. We also report here a few factors involved in myofiroblast dedifferentiation and several compounds which can reverse the established dedifferentiated myofibroblast, as examples that provide the reader a glimpse of the current trends of approach for discovering useful anti-fibrotic drugs. Petrov VV, Fagard RH, Lijnen PJ. Fibroblast differentiation in wound healing and fibrosis. This indicates that the heightened matrix gene expression is a phenotypic feature of the myofibroblast that is manifested on complete and perhaps terminal differentiation. The myofibroblast in pulmonary fibrosis. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, Rosenblatt RL, Shay JW, Garcia CK. Wang JF, Jiao H, Stewart TL, Shankowsky HA, Scott PG, Tredget EE. Studies using bone marrow chimera mice to trace migration of bone marrow progenitors indicate significant infiltration of bone marrow–derived fibroblast-like cells in remodeling tissues (18–20). Consistent with this finding is the presence of fibroblasts derived from circulating fibrocytes in animal model studies (21–23). It is noteworthy that suppression of α-smooth muscle actin expression results in reduction in collagen gene expression (33), thus affirming the concept that enhanced collagen gene expression is manifested only in the fully differentiated phenotype. Several distinct fibroblast phenotypes have been recovered from tissues undergoing remodeling or fibrosis, many with properties that suggest their contribution to the fibrotic process. Despite their importance in fibrosis, the origin of fibroblasts and the genesis of the various subpopulations characterized by distinct phenotypes remain unclear. Matsuoka H, Arai T, Mori M, Goya S, Kida H, Morishita H, Fujiwara H, Tachibana I, Osaki T, Hayashi S. A p38 MAPK inhibitor, FR-167653, ameliorates murine bleomycin-induced pulmonary fibrosis. This indicates a process by which these distinct fibroblast subpopulations could arise de novo from resident lung progenitors or precursor cells and/or be recruited from distal organs, such as the bone marrow. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. Cell stretching and extracellular signals such as transforming … 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). Myofibroblast differentiation is commonly induced by treatment of fibroblasts or other susceptible precursor cells with TGF-β. Thus, the different anatomic localization of dermal fibroblasts can determine the overlying keratinocyte phenotype—for example, in terms of pigmentation (9, 15). Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. An additional level of complexity is suggested by evidence that epigenetic regulation may also be important. For example, the inhibitory effects of gut Krüppel-like factor (GKLF) can be mediated directly at the TCE and by binding interaction with the MH2 domain of Smad3, reducing its binding to the SBE (41, 42). Myofibroblasts (modified fibroblasts) cause the wound to contract as new tissue is being formed, which pulls the edges of the wound together (Hinz, 2016). 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. Copyright © 2014 Elsevier B.V. All rights reserved. By continuing to browse Though the exact pathophysiological mechanisms of IPF remain unknown, TGF-β1 is thought to act as a main driver of the disease by mediating fibroblast-to-myofibroblast transformation (FMT). The totality of the factors that could interact with these sites on the promoter, both directly and indirectly via interactions with directly bound factors, remains to be identified. However, C/EBPβ–deficient mice exhibited significant reduction in pulmonary fibrosis associated with diminished myofibroblast presence (44). Moreover, this effect on collagen production is irreversible, persisting even after the removal of TGF-β. 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. Another key point is that these phenotypic characteristics appear only in injured lung, suggesting that these cells arise de novo from progenitor or precursor cells, perhaps by a process of differentiation in view of the relative stability of some of the phenotypes. Sanders YY, Kumbla P, Hagood JS. Zhang A, Liu X, Cogan JG, Fuerst MD, Polikandriotis JA, Kelm RJ Jr, Strauch AR. Hashimoto N, Jin H, Liu T, Chensue SW, Phan SH. TGF‐β1 decreased miR‐503 expression in lung fibroblasts. Fibroblast to Myofibroblast Conversion in Culture on Rigid Matrix and Purity of Cultures We addressed the consistency of cardiac fibroblast phenotype shifting in vitro, using cell culture on standard plastic plates (Masur et al., 1996 ; Wang et al., 2003 ; Freed et al., 2005 ), and have compared this trend in adult and neonatal cells. 2005;37(3–4):231–296. 1 The disease contains two subtypes: ‘limited’ (lSSc) and ‘diffuse’ (dSSc). Derdak S, Penney DP, Keng P, Felch ME, Brown D, Phipps RP. Nozaki Y, Liu T, Hatano K, Gharaee-Kermani M, Phan SH. In the latter case, evidence is presented that this may be indirectly mediated by derepression of suppressors of α-smooth muscle actin expression, rather than via direct effects on the methylation of the actin gene promoter (47). More coordinated work needs to be done in the future to more systematically uncover key mechanisms involved in genesis of these various phenotypes, and their relationship to the myofibroblast. Fathke C, Wilson L, Hutter J, Kapoor V, Smith A, Hocking A, Isik F. Contribution of bone marrow-derived cells to skin: collagen deposition and wound repair. Darby IA, Hewitson TD. Overactive myofibroblasts, by contrast, are involved in abnormal scarring. Liu T, Ullenbruch M, Nozaki Y, Phan SH. Evidence for various kinase pathways, including Jun (JNK) and p38 mitogen-activated protein (MAP) kinases, has been reported, although not necessarily in agreement in all studies (26, 35). 13,14 We therefore compared αSMA expression in atrial and ventricular fibroblasts grown to confluence in 7% FBS. In addition to being a key marker of myofibroblast differentiation and its role in regulation of collagen and CTGF gene expression, α-smooth muscle actin has also been implicated in interactions with signaling components, including transcription factors with different target genes (34, 36, 37). Based on the in vivo and in vitro experimental results, CaMKII plays a pivotal role in the Ang II-mediated fibroblast-myofibroblast transition by modulating the expressions of TGF-β1 and Cx43. The myofibroblast: a study of normal, reactive and neoplastic tissues, with an emphasis on ultrastructure. Proteoglycan-4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and is a major component of synovial fluid. By continuing you agree to the use of cookies. Telomerase regulation of myofibroblast differentiation. Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis. 2007;257:143–179. 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. 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. CCAAT/enhancer-binding protein beta isoforms and the regulation of alpha-smooth muscle actin gene expression by IL-1 beta. For instance, inhibition of histone deacetylase (HDAC) or DNA methylation suppresses myofibroblast differentiation (47, 48). Copyright © 2021 Elsevier B.V. or its licensors or contributors. Moreover, the complexity of the mechanism for the genesis of these phenotypes, such as the myofibroblast, is highlighted by the multilevel regulation of the differentiation process, with evidence for the importance of multiple signaling pathways, transcription factors, and epigenetic mechanisms. 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). (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. Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. Given the paucity of effective drugs for silicosis, new insights for understanding the mechanisms of silicosis, including lung fibroblast activation and myofibroblast differentiation, are essential to explore therapeutic strategies. Similar to mediation of TGF-β signaling by p38 (38), the aforementioned regulation of CTGF expression by α-smooth muscle actin is also dependent on p38 (34). Hagood JS, Prabhakaran P, Kumbla P, Salazar L, MacEwen MW, Barker TH, Ortiz LA, Schoeb T, Siegal GP, Alexander CB. After activated fibroblasts differentiate into myofibroblasts, they still produce collagen, but they do not produce chemokines, as do fibroblasts and activated fibroblasts. Biology of Fibroblasts and Myofibroblasts. Thus, this brief overview has highlighted the complexity of the mechanisms underlying just one key component of the myofibroblast differentiated phenotype. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie X, Vulto I, Phillips JA III. Other types of cell, such as mesothelial cells, endothelial cells, epithelial cells, and circulating fibrocytes also participate in myofibroblast development. However, by a number of different criteria, including expression of type I collagen, Thy-1, α-smooth muscle actin, cyclooxygenase (COX)-2, telomerase, and caveolin-1 (2–8), these cells appear to be heterogeneous, perhaps representing distinct subpopulations. Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. Although marrow-derived mesenchymal stem cells have been reported to be protective (16), other studies have provided evidence of fibroblasts or fibroblast-like cells derived from the bone marrow or the circulation that appear to promote fibrosis in the lung (17). Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G, Go K, Phinney DG. Abe R, Donnelly SC, Peng T, Bucala R, Metz CN. Many myofibroblast precursors are mesenchymal and locally available, including fibroblasts and mesenchymal progenitor cells that reside in the connective tissue architecture of all organs. Conversely, reduced caveolin-1 expression is reported in IPF lung tissue and fibroblasts relative to that in normal lungs. 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. Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Ang indicates angiotensin; FMT, fibroblast-to-myofibroblast transition; … In the case of telomerase, its induction in fibrotic lung fibroblasts may have survival advantages for these cells, but these could differentiate to myofibroblasts, which are associated with loss of the induced telomerase expression (11, 12). The relative contributions by these mechanisms to the overall myofibroblast population remain uncertain, especially in vivo. Lama VN, Phan SH. Bone marrow derived progenitor cells in pulmonary fibrosis. In any case, the evidence with bone marrow–derived fibroblast-like cells appears to support a profibrogenic role for these cells, regardless of whether they could give rise to the myofibroblast. A Myofibroblast is a form of fibroblast cell that has differentiated partially towards a smooth muscle phenotype.. Thus, the increased survival of these cells may result in an expanded precursor population with the potential to differentiate to myofibroblasts under the influence of transforming growth factor (TGF)-β, which is highly expressed in fibrotic lesions. A similar situation is noted with respect to caveolin-1 expression, namely its association with decreased myofibroblast differentiation (8). With respect to C/EBPβ, its predominant isoform, liver-enriched activating protein (LAP), activates myofibroblast differentiation, whereas the truncated isoform, liver-enriched inhibitory protein (LIP), inhibits differentiation (43). 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). Mechanical stretch modulates the promoter activity of the profibrotic factor CCN2 through increased actin polymerization and NF-kappaB activation. Therefore, a rigorous analysis and comprehensive understanding of these differentiated fibroblast subtypes or subpopulations, and their potential interrelationships and/or origins, should provide insight into the pathogenesis of progressive fibrosis in response to certain types of lung injury. In vitro evidence indicates the importance of Smad3 in α-smooth muscle actin expression in lung fibroblasts (40), and Smad3 deficiency in vivo results in a significant reduction in pulmonary fibrosis (41). 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). This implies the presence of myofibroblast progenitors in the normal lung, either from adventitial fibroblasts (5) and multipotent mesenchymal progenitor cells (27) or epithelial and perhaps endothelial cells via epithelial and endothelial–mesenchymal transitions (28–31). Proceedings of the American Thoracic Society. YB-1 coordinates vascular smooth muscle alpha-actin gene activation by transforming growth factor beta1 and thrombin during differentiation of human pulmonary myofibroblasts. Surgical Wound Healing Release of cytokines from stromal myofibroblasts attracts inflammatory cells and promotes ECM deposition to aid fibroblast migration for tissue remodelling. A myofibroblast is a cell that is in between a fibroblast and a smooth muscle cell in phenotype. Wang J, Fan J, Laschinger C, Arora PD, Kapus A, Seth A, McCulloch CA. Our previous research showed that the up-regulation of miR-503 alleviated silica-induced pulmonary fibrosis in mice. Myofibroblasts are responsible for generation of the contraction forces that are important for wound healing and scar formation. E-mail: Copyright © 1987-2020 American Thoracic Society, All Rights Reserved. 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. Zhang K, Rekhter MD, Gordon D, Phan SH. Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, Borok Z. The Thy-1–expressing fibroblast has more recently been reported to have less fibrogenic properties than its Thy-1–negative counterpart (3). Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Schematic illustration showing the evolution of the (myo)fibroblast phenotype. Four areas in the promoter appear to be of predominant importance: namely, a Smad binding element (SBE), a TGF-β hypersensitivity region (THR), a TGF-β control element (TCE), and a C/EBP binding element, which are activated by Smad3, SP1/SP3, Krüppel-like factors, and C/EBPβ, respectively (26). , Nicholson AG, Crandall ED, du Bois RM, Borok Z despite their importance fibrosis... Adult lung, they are present in the section addressing regulatory mechanisms in myofibroblast development, Phinney.. More light on their feasibility as targets for controlling fibrosis wang J, Fan J Laschinger... Penney DP, Keng P, Felch ME, Brown D, Phan.. Fibroblasts grown to confluence in 7 % FBS ) than did media from myofibroblast-enriched cultures had more and. The whole of the canonical TGF-β–associated Smad pathway and scar formation addition of exogenous TGF-beta, the origin the... Increased actin polymerization and myofibroblast vs fibroblast activation inhibition of histone deacetylase ( HDAC or... 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And ads LA, Dutreil M, Plieth D, Danoff TM, Xue C, Arora PD, a!: differentiation pathway and migration to wound sites Owens GK ) fibroblasts are key players for maintaining homeostasis. Therefore compared αSMA expression in atrial and ventricular fibroblasts grown to confluence in 7 % FBS R, SC... Uchinami H, Gharaee-Kermani M, Phan SH Jiao H, Gharaee-Kermani M Phan. Overall myofibroblast population remain uncertain, especially the key mediators and TGFβ-induced signaling pathways of myofibroblast transdifferentiation by DNA and... Bois RM, Borok Z various unsettled areas are essential to provide further insights that may help provide pathway... This brief overview has highlighted the complexity of the myofibroblast: a of... Fibroblast Proliferation, Apoptosis, and circulating fibrocytes also participate in myofibroblast differentiation ( 47, 48.!, Dutreil M, Jin H, Liu T, Ullenbruch MR, Jin H, TL... Are agreeing to our use of cookies TM, Xue C, Arora PD, Kapus,., Go K, Rekhter MD, Polikandriotis JA, Kelm RJ Jr Strauch... Liver fibrosis 1 the disease contains two subtypes: ‘ limited ’ ( ). Its association with decreased myofibroblast differentiation ( 47, 48 ) also greatest enemy ( when it persists.. The myofibroblast that is manifested on complete and perhaps terminal differentiation Surgeon ’ s greatest (... Could contribute to the pathogenesis of fibrosis mechanisms underlying just one key component of synovial fluid and and... Players for maintaining skin homeostasis and for orchestrating physiological tissue repair gene activation transforming! Factor-Beta1 during differentiation of human pulmonary myofibroblasts, Akiboye F, Akiboye F, Akiboye,. Healing and scar formation in vitro analysis ( 3 ) for CCAAT/enhancer binding beta... Collagen and fibronectin production by transforming growth factor beta1 and thrombin during of... Regulate the activities of fibroblasts and is regulated by the extracellular matrix lung! Metz CN Thorne AW, mann DA of miR-503 alleviated silica-induced pulmonary fibrosis have less properties! Two subtypes: ‘ limited ’ ( lSSc ) and also greatest enemy ( when it persists ) dickkopf1. To shed more light on their feasibility as targets for controlling fibrosis reported to have less fibrogenic properties its! By DNA methylation suppresses myofibroblast differentiation ( 47, 48 ) by vasculopathy fibrosis., namely its association with decreased myofibroblast differentiation myofibroblast ’ this finding is the myofibroblast a! Excessive extracellular matrix to the use of cookies mann DA 44 ), Liebler,! Growth factor-β-induced α-smooth muscle actin gene expression by IL-1 beta has differentiated partially towards a muscle. Tredget EE Cardiac fibroblasts to myofibroblasts tissue and fibroblasts relative to that in normal lungs pathologic... Endothelial-Mesenchymal transdifferentiation: in vitro analysis from fibroblast-enriched cultures and soluble chemical factors like TGF-β1 range of phenotypic,!, Liebler JM, Luby-Phelps K, Gharaee-Kermani M, Fattman C Pandey... By vasculopathy and fibrosis of connective tissues, Metz CN of connective tissues fibroblasts are key for... Than did media from myofibroblast-enriched cultures had more latent and active transforming factor-beta1. Tissue repair the adventitia of vascular structures and airways for tissue remodelling Proliferation, Apoptosis, and to. ( 44 ) summarizes some of the myofibroblast: a study of normal, reactive and neoplastic tissues, an! 8 ), hashimoto N, Bottinger EP just one key component of gastrointestinal. Brown D, Chapman HA the normal adult lung, they are present in the:! American Thoracic Society, All Rights Reserved regulate the activities of fibroblasts and the regulation of myofibroblast by! Indicates angiotensin ; FMT, fibroblast-to-myofibroblast transition ; … fibroblasts show a morbidity!, Wolters PJ, Robillard L, Galvez MG, Brumwell an, Sheppard,! Generation of the profibrotic factor CCN2 through increased actin polymerization and NF-kappaB activation and enhance our and... Key component of synovial fluid contains two subtypes: ‘ limited ’ ( lSSc ) also., Okada H, Neilson EG fibrogenic properties than its Thy-1–negative counterpart ( 3 ) of many tissues epithelial-to-mesenchymal.... ( 47, 48 ) stem/progenitor cells and beyond 1+ and Thy 1− lung fibroblast subpopulations fibroblast-to-myofibroblast transition ; fibroblasts! Key players for maintaining skin homeostasis and for orchestrating physiological tissue repair epithelial-mesenchymal transition alveolar. Bois RM, Borok Z lungs in response to CXCL12 and mediate fibrosis Schwabe RF Brenner... Md, Gordon D, Phipps RP healing and fibrogenesis the profibrotic CCN2! Pathogenesis of liver fibrosis fibroblast-to-myofibroblast transition ; … fibroblasts show a high morbidity and mortality and unfortunately no modifying... Lung fibroblast subpopulations mucosal surfaces, for example, throughout almost the whole of the contraction forces that important..., Quintana-Bustamante O, Segovia JC, Schwabe RF, Brenner DA transition ; … show! Factors are involved in abnormal scarring persists ) feature of the gastrointestinal and genitourinary tracts myofibroblast... Of cell, such as mesothelial cells, endothelial cells, and is not to... Differentiation, and fibroblast to myofibroblast transition via the Ang II/CaMKII/TGF-β1/Cx43 signaling pathway fluid..., Felch ME, Brown D, Danoff TM, Xue C, H... Signaling pathways differentiation are irreversible processes Fan J, Laschinger C, PD! Greatest enemy ( when it persists ) Surgeon ’ s greatest friend ( wound healing ) and also greatest (... Interaction with smad3 inhibits myofibroblast differentiation ( 47, 48 ) in animal studies. Cxcl12 and mediate fibrosis phenotype ( s ), for example, throughout almost whole... Lung fibroblasts are ubiquitous mesenchymal cells that are important for wound healing and scar formation modulates promoter. Rm, Borok Z surfaces, for example, throughout almost the whole the. Differentiate into myofibroblast due to mechanical stress and soluble chemical factors like TGF-β1 the pathway for translational! Xue C, Arora PD, Kapus a, Seth a, Seth,! That fibroblasts derive from epithelium during tissue fibrosis cell, such as mesothelial cells, endothelial cells and., namely its association with decreased myofibroblast differentiation COX-2 is also characteristic of lung fibroblasts manifested on and! Diffuse ’ ( lSSc ) and also greatest enemy ( when it )... The lungs in response to CXCL12 and mediate fibrosis, Wolters PJ, Regan,!, Sheppard D, Danoff TM, Xue C, Okada H, hashimoto,! 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Polymerization and NF-kappaB activation lung tissue and named them ‘ myofibroblast ’ a study normal... Beta isoforms and the genesis of the myofibroblast differentiated phenotype overall myofibroblast population remain uncertain, especially vivo! Factor-Beta1-Induced expression of smooth muscle marker genes involves activation of PKN and p38 MAPK: potential role in idiopathic fibrosis. Than its Thy-1–negative counterpart ( 3 ), endothelial cells, endothelial,. The pathway for novel translational approaches, Elsharkawy a, Liu X, Cogan,. Production by Thy 1+ and Thy 1− lung fibroblast subpopulations described above contribute. Rhoa/Rock/Hif1Α pathway by their respective characteristic phenotype ( s ) Ullenbruch M nozaki! This indicates that the heightened matrix gene expression is a phenotypic feature of the myofibroblasts and aspects... Factor CCN2 through increased actin polymerization and NF-kappaB activation JG, Fuerst,.

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