PRG4 is a ligand of the CD44 receptor. (Myo)fibroblasts are embedded in a sophisticated extracellular matrix (ECM) that they secrete, and a complex and interactive dialogue exists between (myo)fibroblasts and their microenvironment. Fibroblasts show a high range of phenotypic plasticity, including transdifferentiation into myofibroblasts. Here, we discuss the origin of the myofibroblasts and different aspects of their differentiation, especially the key mediators and TGFβ-induced signaling pathways. Zhang A, Liu X, Cogan JG, Fuerst MD, Polikandriotis JA, Kelm RJ Jr, Strauch AR. The well-known effect of TGF-β on α-smooth muscle actin expression and myofibroblast differentiation suggests the importance of the canonical TGF-β–associated Smad pathway. Consistent with this finding is the presence of fibroblasts derived from circulating fibrocytes in animal model studies (21–23). 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). A Myofibroblast is a form of fibroblast cell that has differentiated partially towards a smooth muscle phenotype.. Hu B, Wu Z, Liu T, Ullenbruch MR, Jin H, Phan SH. 5. Myofibroblasts are responsible for generation of the contraction forces that are important for wound healing and scar formation. 4. Wang J, Fan J, Laschinger C, Arora PD, Kapus A, Seth A, McCulloch CA. Fibrocytes from burn patients regulate the activities of fibroblasts. 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). Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease characterized by aberrant fibroblast activation and progressive fibrotic remodelling of the lungs. 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. After activated fibroblasts differentiate into myofibroblasts, they still produce collagen, but they do not produce chemokines, as do fibroblasts and activated fibroblasts. Thus, the myofibroblast, by virtue of its ability to express high levels of cytokines, extracellular matrix, and α-smooth muscle actin, is expected to have key roles in inflammation, connective tissue deposition, and lung tissue mechanics, respectively (10). Notch3 Regulates Cardiac Fibroblast Proliferation, Apoptosis, and Fibroblast to Myofibroblast Transition via the RhoA/ROCK/Hif1α Pathway. A key cell in the pathophysiology of SSc is the myofibroblast. Thus, the α-smooth muscle actin–expressing fibroblast, known as the myofibroblast, is shown to be the predominant source of type I collagen and fibrogenic/inflammatory cytokines in fibrotic lesions, as well as imparting altered mechanical properties to affected tissues (5, 10). Ang indicates angiotensin; FMT, fibroblast-to-myofibroblast transition; … Adam PJ, Regan CP, Hautmann MB, Owens GK. 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. 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). 1 The disease contains two subtypes: ‘limited’ (lSSc) and ‘diffuse’ (dSSc). 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. However, C/EBPβ–deficient mice exhibited significant reduction in pulmonary fibrosis associated with diminished myofibroblast presence (44). Bone marrow derived progenitor cells in pulmonary fibrosis. Copyright © 2021 Elsevier B.V. or its licensors or contributors. Proteoglycan-4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and is a major component of synovial fluid. Notes: The myofibroblastic modulation of fibroblastic cells begins with the appearance of the proto myofibroblast, whose stress fibers contain only β- and γ-cytoplasmic actins and evolves, but not necessarily always, into the appearance of the differentiated myofibroblast, the most common … 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. Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Overactive myofibroblasts, by contrast, are involved in abnormal scarring. Nozaki Y, Liu T, Hatano K, Gharaee-Kermani M, Phan SH. Evidence for these possibilities is reviewed, but there is as yet incomplete understanding of the precise precursor cells and the potential interrelationships between the various phenotypes, especially as to how they relate to the distinct myofibroblast phenotype. We conclude that Ang II mediates the fibroblast-myofibroblast transition partially via the Ang II/CaMKII/TGF-β1/Cx43 signaling pathway. Hinz B, Gabbiani G, Chaponnier C. The NH2-terminal peptide of alpha-smooth muscle actin inhibits force generation by the myofibroblast in vitro and in vivo. 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. Liu T, Ullenbruch M, Nozaki Y, Phan SH. By continuing you agree to the use of cookies. 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). Telomerase regulation of myofibroblast differentiation. Int Rev Cytol. In the normal adult lung, they are present in the adventitia of vascular structures and airways. Differential collagen and fibronectin production by Thy 1+ and Thy 1− lung fibroblast subpopulations. 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. Conversely, reduced caveolin-1 expression is reported in IPF lung tissue and fibroblasts relative to that in normal lungs. Myofibroblasts (modified fibroblasts) cause the wound to contract as new tissue is being formed, which pulls the edges of the wound together (Hinz, 2016). Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Enhanced myofibroblastic differentiation and survival in Thy-1(−) lung fibroblasts. Additional factors that may play a role include the Notch signaling pathway, which appears to be important in epithelial–mesenchymal transition (45), whereas YB-1 (Y-box binding protein-1), NF-κB, and PPARγ (peroxisome proliferator activated receptor-γ) may be important in suppressing differentiation (46, 47). Induction of telomerase activity in fibroblasts from bleomycin-injured lungs. 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). Wilborn J, Crofford LJ, Burdick MD, Kunkel SL, Strieter RM, Peters-Golden M. Cultured lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize prostaglandin E2 and to express cyclooxygenase-2. Future studies into these various unsettled areas are essential to provide further insights that may help provide the pathway for novel translational approaches. Regulation of telomerase activity in lung fibroblasts. Katzenstein AA, Myers JL. 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). The myofibroblast is an intermediate cell between the fibroblast and the smooth muscle cell (Gabbiani et al., 1971) and myofibroblasts have been demonstrated as the main effectors of fibrosis in all tissues (Shirol and Shirol, 2012). The relative contributions by these mechanisms to the overall myofibroblast population remain uncertain, especially in vivo. Myofibroblast differentiation is commonly induced by treatment of fibroblasts or other susceptible precursor cells with TGF-β. CCAAT/enhancer-binding protein beta isoforms and the regulation of alpha-smooth muscle actin gene expression by IL-1 beta. 13,14 We therefore compared αSMA expression in atrial and ventricular fibroblasts grown to confluence in 7% FBS. An additional level of complexity is suggested by evidence that epigenetic regulation may also be important. There is evidence that TGF-β stimulation of fibroblast collagen production is a consequence of myofibroblast differentiation—that is, that acquisition of the myofibroblast phenotype is necessary for the increased collagen production (32). 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). Stimulation of collagen production by transforming growth factor-beta1 during differentiation of cardiac fibroblasts to myofibroblasts. Darby IA, Hewitson TD. Thus, in three of these phenotypes, namely those expressing low levels (or none) of Thy-1, caveolin-1, or COX-2, their differentiation to a fibrotic phenotype(s) is associated with loss of antifibrotic phenotypes, rather than a gain or activation of fibrotic phenotypes. Mechanical stretch modulates the promoter activity of the profibrotic factor CCN2 through increased actin polymerization and NF-kappaB activation. Myofibroblasts are found subepithelially in many mucosal surfaces, for example, throughout almost the whole of the gastrointestinal and genitourinary tracts. The resident tissue fibroblast as a source of myofibroblasts has been documented extensively in multiple tissues, primarily by studies of these cells in tissue culture, wherein myofibroblast differentiation can be induced by treatment with TGF-β and other cytokines (26). Thus, relief from inhibition as well as activation by stimulatory transcription factors may be operative in myofibroblast differentiation. The fibroblast/myofibroblast transition is accepted as the key event in the formation of granulation tissue during wound healing or fibrotic changes, but also during the evolution of the stroma reaction in cancer. Previous paragraphs have summarized recent evidence of the potentially diverse cellular origins of the myofibroblast, whereas this section summarizes recent progress on the mechanisms involved in myofibroblast differentiation. 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). 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). Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, Chapman HA. Lama VN, Phan SH. Phan SH. Structure. Abe R, Donnelly SC, Peng T, Bucala R, Metz CN. By continuing to browse 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. Zhang K, Rekhter MD, Gordon D, Phan SH. 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. 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). 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. 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). 2007;257:143–179. Various studies have described distinct and relatively stable phenotypes in fibroblasts isolated from lung tissue undergoing remodeling, which were not present in the normal intact tissue. This site uses cookies. Systemic sclerosis (SSc) is a severe auto-immune disease, characterized by vasculopathy and fibrosis of connective tissues. 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. SSc has a high morbidity and mortality and unfortunately no disease modifying therapy is currently available. An essential role for CCAAT/enhancer binding protein beta in bleomycin-induced pulmonary fibrosis. THE ROLES OF DIFFERENTIATED FIBROBLAST SUBPOPULATIONS. 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 –. 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. Smad3 mediates transforming growth factor-β-induced α-smooth muscle actin expression. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Moreover, this effect on collagen production is irreversible, persisting even after the removal of TGF-β. However, recent data obtained indicates that tissue fibrosis and fibroblast-to-myofibroblast differentiation can indeed be reversed, which offers the possibility of a new therapeutic approach for fibrotic disorders. This issue is further discussed below in the section addressing regulatory mechanisms in myofibroblast differentiation. 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. 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. Cell stretching and extracellular signals such as transforming … 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. 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. 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. Several distinct fibroblast phenotypes have been recovered from tissues undergoing remodeling or fibrosis, many with properties that suggest their contribution to the fibrotic process. The mechanisms of fibroblast-to-myofibroblast conversion have been extensively studied in vitro despite the fact that, with time in culture, cardiac fibroblasts spontaneously attain a myofibroblast phenotype and significantly upregulate α-SMA expression. Smooth muscle actin determines mechanical force-induced p38 activation. 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). Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Fibroblast differentiation in wound healing and fibrosis. However, in the context of fibroblast–epithelial cross-talk, as postulated for cellular components of the fibroblastic foci, there is recent evidence that the fibroblastic elements underlying epithelium have considerable influence on the epithelial phenotype. Biology of Fibroblasts and Myofibroblasts. (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. Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP. Other types of cell, such as mesothelial cells, endothelial cells, epithelial cells, and circulating fibrocytes also participate in myofibroblast development. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. A myofibroblast is a cell that is in between a fibroblast and a smooth muscle cell in phenotype. Our previous research showed that the up-regulation of miR-503 alleviated silica-induced pulmonary fibrosis in mice. This indicates that the heightened matrix gene expression is a phenotypic feature of the myofibroblast that is manifested on complete and perhaps terminal differentiation. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Submicrosc Cytol Pathol. 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. 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. Frid MG, Kale VA, Stenmark KR. 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). Sanders YY, Kumbla P, Hagood JS. Hu B, Wu Z, Jin H, Hashimoto N, Liu T, Phan SH. Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, Belperio JA, Keane MP, Strieter RM. Myofibroblast Markers . , we discuss the origin of fibroblasts derived from circulating fibrocytes in animal model studies ( 21–23 ) and terminal! Mecp2: implications for wound healing Release of cytokines from stromal myofibroblasts attracts inflammatory cells and beyond K, DG..., Tredget EE, Keng P, Felch ME, Brown D, Phan SH and unfortunately disease! 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Collagen production is irreversible, persisting even after the removal of TGF-β on muscle... Some of the various subpopulations characterized by vasculopathy and fibrosis of connective tissues complexity of the and! With respect to caveolin-1 expression is reported in IPF lung tissue and named ‘. Auto-Immune disease, characterized by dysregulated fibroblast to myofibroblast transition via the Ang II/CaMKII/TGF-β1/Cx43 signaling pathway Elsevier... Myofibroblasts after addition of exogenous TGF-beta, the results did not reach statistical significance results not. Fibroblast Proliferation, Apoptosis, and circulating fibrocytes also participate in pathogenesis liver...