Hostname: page-component-f554764f5-nwwvg Total loading time: 0 Render date: 2025-04-09T23:53:34.580Z Has data issue: false hasContentIssue false
  • English
  • Français

Myofibroblast differentiation and survival in fibrotic disease

Published online by Cambridge University Press:  23 August 2011

Kornelia Kis ,
Xiaoqiu Liu  and
James S. Hagood
Kornelia Kis
Affiliation:
Department of Pediatrics, Division of Respiratory Medicine, University of California-San Diego, San Diego, CA, USA
Xiaoqiu Liu
Affiliation:
Department of Pediatrics, Division of Respiratory Medicine, University of California-San Diego, San Diego, CA, USA
James S. Hagood*
Affiliation:
Department of Pediatrics, Division of Respiratory Medicine, University of California-San Diego, San Diego, CA, USA Rady Children's Hospital of San Diego, San Diego, CA, USA
*
*Corresponding author: James S. Hagood, University of California-San Diego, 9500 Gilman Drive, MC 0731, San Diego, CA 92093-0731. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

During wound healing, contractile fibroblasts called myofibroblasts regulate the formation and contraction of granulation tissue; however, pathological and persistent myofibroblast activation, which occurs in hypertrophic scars or tissue fibrosis, results in a loss of function. Many reviews outline the cellular and molecular features of myofibroblasts and their roles in a variety of diseases. This review focuses on the origins of myofibroblasts and the factors that control their differentiation and prolonged survival in fibrotic tissues. Pulmonary fibrosis is used to illustrate many key points, but examples from other tissues and models are also included. Myofibroblasts originate mostly from tissue-resident fibroblasts, and also from epithelial and endothelial cells or other mesenchymal precursors. Their differentiation is influenced by cytokines, growth factors, extracellular matrix composition and stiffness, and cell surface molecules such as proteoglycans and THY1, among other factors. Many of these effects are modulated by cell contraction. Myofibroblasts resist programmed cell death, which promotes their accumulation in fibrotic tissues. The cause of resistance to apoptosis in myofibroblasts is under ongoing investigation, but many of the same stimuli that regulate their differentiation are involved. The contributions of oxidative stress, the WNT–β-catenin pathway and PPARγ to myofibroblast differentiation and survival are increasingly appreciated.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 13 , March 2011 , e27
Copyright
Copyright © Cambridge University Press 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

References

1Clark, R.A.F. (1996) Wound repair: overview and general considerations. In The Molecular and Cellular Biology of Wound Repair (Clark, R.A.F., ed.), pp. 3-50, Plenum Press, New YorkGoogle Scholar
2Gabbiani, G. (2003) The myofibroblast in wound healing and fibrocontractive diseases. Journal of Pathology 200, 500-503CrossRefGoogle ScholarPubMed
3Hardie, W.D., Glasser, S.W. and Hagood, J.S. (2009) Emerging concepts in the pathogenesis of lung fibrosis. American Journal of Pathology 175, 3-16Google Scholar
4Hinz, B. (2007) Formation and function of the myofibroblast during tissue repair. Journal of Investigative Dermatology 127, 526-537CrossRefGoogle ScholarPubMed
5Thiery, J.P. et al. (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139, 871-890CrossRefGoogle ScholarPubMed
6Kalluri, R. and Neilson, E.G. (2003) Epithelial-mesenchymal transition and its implications for fibrosis. Journal of Clinical Investigation 112, 1776-1784CrossRefGoogle ScholarPubMed
7Zavadil, J. and Böttinger, E.P. (2005) TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 24, 5764-5774CrossRefGoogle ScholarPubMed
8Iwano, M. et al. (2002) Evidence that fibroblasts derive from epithelium during tissue fibrosis. Journal of Clinical Investigation 110, 341-350Google Scholar
9Osterreicher, C.H. et al. (2011) Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proceedings of the National Academy of Sciences of the United States of America 108, 308-313Google Scholar
10Zeisberg, M. et al. (2007) Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. Journal of Biological Chemistry 282, 23337-23347CrossRefGoogle ScholarPubMed
11Zeisberg, E.M. et al. (2007) Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature Medicine 13, 952-961CrossRefGoogle ScholarPubMed
12Zeisberg, E.M. et al. (2008) Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. Journal of the American Society of Nephrology 19, 2282-2287CrossRefGoogle ScholarPubMed
13Kim, K.K. et al. (2009) Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. Journal of Clinical Investigation 119, 213-224Google ScholarPubMed
14Câmara, J. and Jarai, G. (2010) Epithelial-mesenchymal transition in primary human bronchial epithelial cells is Smad-dependent and enhanced by fibronectin and TNF-alpha. Fibrogenesis & Tissue Repair 3, 2Google Scholar
15Scholten, D. et al. (2010) Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice. Gastroenterology 139, 987-998CrossRefGoogle Scholar
16Humphreys, B.D. et al. (2010) Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. American Journal of Pathology 176, 85-97CrossRefGoogle Scholar
17Tanjore, H. et al. (2009) Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis. American Journal of Respiratory and Critical Care Medicine 180, 657-665CrossRefGoogle ScholarPubMed
18Li, J. and Bertram, J.F. (2010) Review: endothelial–myofibroblast transition, a new player in diabetic renal fibrosis. Nephrology (Carlton, Victoria) 15, 507-512Google Scholar
19Nataraj, D., Ernst, A. and Kalluri, R. (2010) Idiopathic pulmonary fibrosis is associated with endothelial to mesenchymal transition. American Journal of Respiratory Cell and Molecular Biology 43, 129-130CrossRefGoogle ScholarPubMed
20Potenta, S., Zeisberg, E. and Kalluri, R. (2008) The role of endothelial-to-mesenchymal transition in cancer progression. British Journal of Cancer 99, 1375-1379CrossRefGoogle ScholarPubMed
21Widyantoro, B. et al. (2010) Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition. Circulation 121, 2407-2418CrossRefGoogle ScholarPubMed
22Hashimoto, N. et al. (2010) Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. American Journal of Respiratory Cell and Molecular Biology 43, 161-172CrossRefGoogle ScholarPubMed
23Arciniegas, E. et al. (2007) Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension. American Journal of Physiology. Lung Cellular and Molecular Physiology 293, L1-L8CrossRefGoogle ScholarPubMed
24Hashimoto, N. et al. (2004) Bone marrow-derived progenitor cells in pulmonary fibrosis. Journal of Clinical Investigation 113, 243-252Google Scholar
25Moeller, A. et al. (2009) Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 179, 588-594Google Scholar
26Moore, B.B. et al. (2005) CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury. American Journal of Pathology 166, 675-684CrossRefGoogle Scholar
27Andersson-Sjöland, A. et al. (2008) Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis. The International Journal of Biochemistry and Cell Biology 40, 2129-2140CrossRefGoogle ScholarPubMed
28García-de-Alba, C. et al. (2010) Expression of matrix metalloproteases by fibrocytes: possible role in migration and homing. American Journal of Respiratory and Critical Care Medicine 182, 1144-1152CrossRefGoogle ScholarPubMed
29Phillips, R.J. et al. (2004) Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. Journal of Clinical Investigation 114, 438-446CrossRefGoogle Scholar
30Abe, R. et al. (2001) Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. Journal of Immunology 166, 7556-7562CrossRefGoogle ScholarPubMed
31Strieter, R.M. et al. (2009) The role of circulating mesenchymal progenitor cells, fibrocytes, in promoting pulmonary fibrosis. Transactions of the American Clinical and Climatological Association 120, 49-59Google ScholarPubMed
32Asanuma, H. et al. (2011) Arterially delivered mesenchymal stem cells prevent obstruction-induced renal fibrosis. Journal of Surgical Research 168, e51-e59CrossRefGoogle ScholarPubMed
33Popova, A.P. et al. (2010) Autocrine production of TGF-beta1 promotes myofibroblastic differentiation of neonatal lung mesenchymal stem cells. American Journal of Physiology. Lung Cellular and Molecular Physiology 298, L735-L743CrossRefGoogle ScholarPubMed
34Lee, C.H. et al. (2010) CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model. Journal of Clinical Investigation 120, 3340-3349CrossRefGoogle Scholar
35Atamas, S.P. and White, B. (2003) Cytokine regulation of pulmonary fibrosis in scleroderma. Cytokine and Growth Factor Reviews 14, 537-550CrossRefGoogle ScholarPubMed
36Knight, D.A. et al. (2003) The role of gp130/IL-6 cytokines in the development of pulmonary fibrosis: critical determinants of disease susceptibility and progression? Pharmacology and Therapeutics 99, 327-338Google Scholar
37Lasky, J.A. and Brody, A.R. (2000) Interstitial fibrosis and growth factors. Environmental Health Perspectives 108 (Suppl 4), 751-762Google Scholar
38Yang, L. et al. (2008) IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 454, 350-352Google Scholar
39Wilson, M.S. et al. (2010) Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent. Journal of Experimental Medicine 207, 535-552Google Scholar
40Yagi, Y. et al. (2007) Inflammatory responses induced by interleukin-17 family members in human colonic subepithelial myofibroblasts. Journal of Gastroenterology 42, 746-753Google Scholar
41Turner, N.A. et al. (2009) Interleukin-1alpha stimulates proinflammatory cytokine expression in human cardiac myofibroblasts. American Journal of Physiology. Heart and Circulatory Physiology 297, H1117-H1127Google Scholar
42Collard, H.R. et al. (2010) Plasma biomarker profiles in acute exacerbation of idiopathic pulmonary fibrosis. American Journal of Physiology. Lung Cellular and Molecular Physiology 299, L3-L7CrossRefGoogle ScholarPubMed
43Huaux, F. et al. (2003) Dual roles of IL-4 in lung injury and fibrosis. Journal of Immunology 170, 2083-2092CrossRefGoogle ScholarPubMed
44Zhou, Y., Hagood, J.S. and Murphy-Ullrich, J.E. (2004) Thy-1 expression regulates the ability of rat lung fibroblasts to activate transforming growth factor-{beta} in response to fibrogenic stimuli. American Journal of Pathology 165, 659-669Google Scholar
45Waddington, S.N. et al. (2010) Gene delivery of a mutant TGFβ3 reduces markers of scar tissue formation after cutaneous wounding. Molecular Therapy: The Journal of the American Society of Gene Therapy 18, 2104-2111Google Scholar
46Liu, X., Kelm, R.J. and Strauch, A.R. (2009) Transforming growth factor beta1-mediated activation of the smooth muscle alpha-actin gene in human pulmonary myofibroblasts is inhibited by tumor necrosis factor-alpha via mitogen-activated protein kinase kinase 1-dependent induction of the Egr-1 transcriptional repressor. Molecular Biology of the Cell 20, 2174-2185CrossRefGoogle ScholarPubMed
47Bhatnagar, S. et al. (2010) Transforming growth factor-beta-activated kinase 1 is an essential regulator of myogenic differentiation. Journal of Biological Chemistry 285, 6401-6411Google Scholar
48Liu, T. et al. (2004) FIZZ1 stimulation of myofibroblast differentiation. American Journal of Pathology 164, 1315-1326Google Scholar
49Lin, X. et al. (2010) Yin Yang 1 is a novel regulator of pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 183, 1689-1697Google Scholar
50Hagood, J.S. et al. (2005) Loss of fibroblast Thy-1 expression correlates with lung fibrogenesis. American Journal of Pathology 167, 365-379Google Scholar
51Sanders, Y.Y. et al. (2008) Epigenetic regulation mediates thy-1 gene silencing and induction of the myofibroblast phenotype. Proceedings of the American Thoracic Society 5, 363-364Google Scholar
52Sanders, Y.Y., Kumbla, P. and Hagood, J.S. (2007) Enhanced myofibroblastic differentiation and survival in Thy-1(-) lung fibroblasts. American Journal of Respiratory Cell and Molecular Biology 36, 226-235CrossRefGoogle ScholarPubMed
53Sanders, Y.Y. et al. (2008) Thy-1 promoter hypermethylation: a novel epigenetic pathogenic mechanism in pulmonary fibrosis. American Journal of Respiratory Cell and Molecular Biology 39, 610-618Google Scholar
54Zhou, Y. et al. (2010) Thy-1-integrin alphav beta5 interactions inhibit lung fibroblast contraction-induced latent transforming growth factor-beta1 activation and myofibroblast differentiation. Journal of Biological Chemistry 285, 22382-22393Google Scholar
55Koumas, L. et al. (2003) Thy-1 expression in human fibroblast subsets defines myofibroblastic or lipofibroblastic phenotypes. American Journal of Pathology 163, 1291-1300CrossRefGoogle ScholarPubMed
56Lehmann, G.M. et al. (2010) Novel anti-adipogenic activity produced by human fibroblasts. American Journal of Physiology. Cell Physiology 299, C672-C681Google Scholar
57Eckes, B. et al. (2006) Mechanical tension and integrin alpha 2 beta 1 regulate fibroblast functions. Journal of Investigative Dermatology. Symposium Proceedings/the Society for Investigative Dermatology, Inc. [and] European Society for Dermatological Research 11, 66-72Google Scholar
58Tomasek, J.J. et al. (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nature Reviews. Molecular Cell Biology 3, 349-363CrossRefGoogle ScholarPubMed
59Katsumi, A. et al. (2004) Integrins in mechanotransduction. Journal of Biological Chemistry 279, 12001-12004Google Scholar
60Jenkins, R.G. et al. (2006) Ligation of protease-activated receptor 1 enhances alpha(v)beta6 integrin-dependent TGF-beta activation and promotes acute lung injury. Journal of Clinical Investigation 116, 1606-1614Google Scholar
61Wang, X. et al. (2009) Silencing CD36 gene expression results in the inhibition of latent-TGF-beta1 activation and suppression of silica-induced lung fibrosis in the rat. Respiratory Research 10, 36CrossRefGoogle ScholarPubMed
62Wipff, P.-J. et al. (2007) Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. Journal of Cell Biology 179, 1311-1323Google Scholar
63Zhou, Y. et al. (2009) Latent transforming growth factor-beta-binding protein-4 regulates transforming growth factor-beta1 bioavailability for activation by fibrogenic lung fibroblasts in response to bleomycin. American Journal of Pathology 174, 21-33Google Scholar
64Giancotti, F.G. and Ruoslahti, E. (1999) Integrin signaling. Science 285, 1028-1032CrossRefGoogle ScholarPubMed
65Choi, S.S. et al. (2010) Activation of Rac1 promotes hedgehog-mediated acquisition of the myofibroblastic phenotype in rat and human hepatic stellate cells. Hepatology 52, 278-290CrossRefGoogle ScholarPubMed
66Margadant, C. and Sonnenberg, A. (2010) Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Reports 11, 97-105Google Scholar
67Chan, M.W.C. et al. (2010) Force-induced myofibroblast differentiation through collagen receptors is dependent on mammalian diaphanous (mDia). Journal of Biological Chemistry 285, 9273-9281Google Scholar
68Follonier Castella, L. et al. (2010) Regulation of myofibroblast activities: calcium pulls some strings behind the scene. Experimental Cell Research 316, 2390-2401Google Scholar
69Couchman, J.R. and Woods, A. (1996) Syndecans, signaling, and cell adhesion. Journal of Cellular Biochemistry 61, 578-5843.0.CO;2-C>CrossRefGoogle ScholarPubMed
70Yoneda, A. and Couchman, J.R. (2003) Regulation of cytoskeletal organization by syndecan transmembrane proteoglycans. Matrix Biology: Journal of the International Society for Matrix Biology 22, 25-33Google Scholar
71Kennedy, L. et al. (2007) CCN2 is necessary for the function of mouse embryonic fibroblasts. Experimental Cell Research 313, 952-964Google Scholar
72Jiang, D. et al. (2010) Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4. Journal of Clinical Investigation 120, 2049-2057Google Scholar
73Avalos, A.M. et al. (2009) Neuronal Thy-1 induces astrocyte adhesion by engaging syndecan-4 in a cooperative interaction with alphavbeta3 integrin that activates PKCalpha and RhoA. Journal of Cell Science 122, 3462-3471CrossRefGoogle Scholar
74Leto, T.L. et al. (2009) Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases. Antioxidants and Redox Signaling 11, 2607-2619Google Scholar
75Kinnula, V.L. et al. (2005) Oxidative stress in pulmonary fibrosis: a possible role for redox modulatory therapy. American Journal of Respiratory and Critical Care Medicine 172, 417-422Google Scholar
76Hecker, L. et al. (2009) NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nature Medicine 15, 1077-1081Google Scholar
77Cucoranu, I. et al. (2005) NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circulation Research 97, 900-907CrossRefGoogle ScholarPubMed
78Amara, N. et al. (2010) NOX4/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis and mediates TGFbeta1-induced fibroblast differentiation into myofibroblasts. Thorax 65, 733-738Google Scholar
79Toullec, A. et al. (2010) Oxidative stress promotes myofibroblast differentiation and tumour spreading. EMBO Molecular Medicine 2, 211-230Google Scholar
80Van Rheen, Z. et al. (2011) Lung extracellular superoxide dismutase overexpression lessens bleomycin-induced pulmonary hypertension and vascular remodeling. American Journal of Respiratory Cell and Molecular Biology 44, 500-508Google Scholar
81Burgess, H.A. et al. (2005) PPARgamma agonists inhibit TGF-beta induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis. American Journal of Physiology. Lung Cellular and Molecular Physiology 288, L1146-L1153CrossRefGoogle ScholarPubMed
82Milam, J.E. et al. (2008) PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis. American Journal of Physiology. Lung Cellular and Molecular Physiology 294, L891-L901Google Scholar
83Lin, Q. et al. (2010) Rosiglitazone inhibits migration, proliferation, and phenotypic differentiation in cultured human lung fibroblasts. Experimental Lung Research 36, 120-128Google Scholar
84Kulkarni, A.A. et al. (2011) PPAR-γ ligands repress TGFβ-induced myofibroblast differentiation by targeting the PI3K/Akt pathway: implications for therapy of fibrosis. PLoS One 6, e15909CrossRefGoogle ScholarPubMed
85Ferguson, H.E. et al. (2009) Electrophilic peroxisome proliferator-activated receptor-gamma ligands have potent antifibrotic effects in human lung fibroblasts. American Journal of Respiratory Cell and Molecular Biology 41, 722-730CrossRefGoogle ScholarPubMed
86Ferguson, H.E. et al. (2009) Peroxisome proliferator-activated receptor-gamma ligands induce heme oxygenase-1 in lung fibroblasts by a PPARgamma-independent, glutathione-dependent mechanism. American Journal of Physiology. Lung Cellular and Molecular Physiology 297, L912-L919Google Scholar
87Fagone, E. et al. (2011) Resveratrol inhibits transforming growth factor-beta-induced proliferation and differentiation of ex vivo human lung fibroblasts into myofibroblasts through ERK/Akt inhibition and PTEN restoration. Experimental Lung Research 37, 162-174Google Scholar
88Kikuchi, A., Yamamoto, H. and Kishida, S. (2007) Multiplicity of the interactions of Wnt proteins and their receptors. Cellular Signalling 19, 659-671Google Scholar
89Chang, W. et al. (2010) SPARC suppresses apoptosis of idiopathic pulmonary fibrosis fibroblasts through constitutive activation of beta-catenin. Journal of Biological Chemistry 285, 8196-8206CrossRefGoogle ScholarPubMed
90He, W. et al. (2009) Wnt/beta-catenin signaling promotes renal interstitial fibrosis. Journal of the American Society of Nephrology 20, 765-776Google Scholar
91Lee, S.H. et al. (2010) ERK activation drives intestinal tumorigenesis in Apc(min/+) mice. Nature Medicine 16, 665-670Google Scholar
92Egger, G. et al. (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457-463CrossRefGoogle ScholarPubMed
93Reik, W. (2007) Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447, 425-432Google Scholar
94Laurent, L. et al. (2010) Dynamic changes in the human methylome during differentiation. Genome Research 20, 320-331Google Scholar
95Wang, Y., Fan, P.S. and Kahaleh, B. (2006) Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis and Rheumatism 54, 2271-2279Google Scholar
96Glenisson, W., Castronovo, V. and Waltregny, D. (2007) Histone deacetylase 4 is required for TGFbeta1-induced myofibroblastic differentiation. Biochimica et Biophysica Acta 1773, 1572-1582Google Scholar
97Guo, W. et al. (2009) Abrogation of TGF-beta1-induced fibroblast-myofibroblast differentiation by histone deacetylase inhibition. American Journal of Physiology. Lung Cellular and Molecular Physiology 297, L864-L870Google Scholar
98Hu, B. et al. (2010) Epigenetic regulation of myofibroblast differentiation by DNA methylation. American Journal of Pathology 177, 21-28Google Scholar
99van Rooij, E. et al. (2008) Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proceedings of the National Academy of Sciences of the United States of America 105, 13027-13032CrossRefGoogle ScholarPubMed
100Liu, G. et al. (2010) miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. Journal of Experimental Medicine 207, 1589-1597Google Scholar
101Yao, Q. et al. (2011) Micro-RNA-21 regulates TGF-beta-induced myofibroblast differentiation by targeting PDCD4 in tumor-stroma interaction. International Journal of Cancer 128, 1783-1792Google Scholar
102Mann, J. et al. (2010) MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 138, 705-714, 714 e701–704Google Scholar
103Chabaud, S. et al. (2011) Decreased secretion of MMP by non-lesional late-stage scleroderma fibroblasts after selection via activation of the apoptotic fas-pathway. Journal of Cellular Physiology 226, 1907-1914Google Scholar
104Fattman, C.L. (2008) Apoptosis in pulmonary fibrosis: too much or not enough? Antioxidants and Redox Signaling 10, 379-385Google Scholar
105Maher, T.M. et al. (2010) Diminished prostaglandin E2 contributes to the apoptosis paradox in idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 182, 73-82Google Scholar
106Jinta, T. et al. (2010) The pathogenesis of chronic hypersensitivity pneumonitis in common with idiopathic pulmonary fibrosis: expression of apoptotic markers. American Journal of Clinical Pathology 134, 613-620CrossRefGoogle ScholarPubMed
107Kuhn, C. and McDonald, J.A. (1991) The roles of the myofibroblast in idiopathic pulmonary fibrosis. Ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis. American Journal of Pathology 138, 1257-1265Google Scholar
108Drakopanagiotakis, F. et al. (2008) Apoptosis in lung injury and fibrosis. European Respiratory Journal 32, 1631-1638CrossRefGoogle ScholarPubMed
109Beon, M. et al. (2004) Myofibroblast induction and microvascular alteration in scleroderma lung fibrosis. Clinical and Experimental Rheumatology 22, 733-742Google Scholar
110Uhal, B.D. (2002) Apoptosis in lung fibrosis and repair. Chest 122, 293S-298SGoogle Scholar
111Vittal, R. et al. (2005) Modulation of prosurvival signaling in fibroblasts by a protein kinase inhibitor protects against fibrotic tissue injury. American Journal of Pathology 166, 367-375Google Scholar
112Horowitz, J.C. et al. (2004) Activation of the pro-survival phosphatidylinositol 3-kinase/AKT pathway by transforming growth factor-beta1 in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine growth factor. Journal of Biological Chemistry 279, 1359-1367Google Scholar
113Garneau-Tsodikova, S. and Thannickal, V.J. (2008) Protein kinase inhibitors in the treatment of pulmonary fibrosis. Current Medicinal Chemistry 15, 2632-2640CrossRefGoogle ScholarPubMed
114Vuga, L.J. et al. (2009) WNT5A is a regulator of fibroblast proliferation and resistance to apoptosis. American Journal of Respiratory Cell and Molecular Biology 41, 583-589Google Scholar
115Xia, H. et al. (2010) Pathologic caveolin-1 regulation of PTEN in idiopathic pulmonary fibrosis. American Journal of Pathology 176, 2626-2637Google Scholar
116Huang, S.K. et al. (2009) Prostaglandin E(2) induces fibroblast apoptosis by modulating multiple survival pathways. FASEB Journal 23, 4317-4326Google Scholar
117Wynes, M.W., Frankel, S.K. and Riches, D.W. (2004) IL-4-induced macrophage-derived IGF-I protects myofibroblasts from apoptosis following growth factor withdrawal. Journal of Leukocyte Biology 76, 1019-1027Google Scholar
118Selman, M. and Pardo, A. (2004) Idiopathic pulmonary fibrosis: misunderstandings between epithelial cells and fibroblasts? Sarcoidosis, Vasculitis and Diffuse Lung Diseases 21, 165-172Google Scholar
119Chapman, H.A. (2011) Epithelial-mesenchymal interactions in pulmonary fibrosis. Annual Review of Physiology 73, 413-435Google Scholar
120Horowitz, J.C. and Thannickal, V.J. (2006) Epithelial-mesenchymal interactions in pulmonary fibrosis. Seminars in Respiratory and Critical Care Medicine 27, 600-612CrossRefGoogle ScholarPubMed
121Selman, M. and Pardo, A. (2006) Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers. Proceedings of the American Thoracic Society 3, 364-372Google Scholar
122Golan-Gerstl, R. et al. (2007) Epithelial cell apoptosis by fas ligand-positive myofibroblasts in lung fibrosis. American Journal of Respiratory Cell and Molecular Biology 36, 270-275Google Scholar
123Kuwano, K. et al. (1999) Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis. Journal of Clinical Investigation 104, 13-19Google Scholar
124Aoshiba, K. et al. (2000) The Fas/Fas-ligand system is not required for bleomycin-induced pulmonary fibrosis in mice. American Journal of Respiratory and Critical Care Medicine 162, 695-700Google Scholar
125Moodley, Y.P. et al. (2004) Comparison of the morphological and biochemical changes in normal human lung fibroblasts and fibroblasts derived from lungs of patients with idiopathic pulmonary fibrosis during FasL-induced apoptosis. Journal of Pathology 202, 486-495CrossRefGoogle ScholarPubMed
126Buhling, F. et al. (2005) Altered expression of membrane-bound and soluble CD95/Fas contributes to the resistance of fibrotic lung fibroblasts to FasL induced apoptosis. Respiratory Research 6, 37Google Scholar
127Kolodsick, J.E. et al. (2003) Prostaglandin E2 inhibits fibroblast to myofibroblast transition via E. prostanoid receptor 2 signaling and cyclic adenosine monophosphate elevation. American Journal of Respiratory Cell and Molecular Biology 29, 537-544Google Scholar
128Wilborn, J. et al. (1995) Cultured lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize prostaglandin E2 and to express cyclooxygenase-2. Journal of Clinical Investigation 95, 1861-1868Google Scholar
129Horowitz, J.C. and Peters-Golden, M. (2010) Prostaglandin E2's new trick: “decider” of differential alveolar cell life and death. American Journal of Respiratory and Critical Care Medicine 182, 2-3Google Scholar
130Hagimoto, N. et al. (2002) TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells. Journal of Immunology 168, 6470-6478Google Scholar
131Chodon, T. et al. (2000) Keloid-derived fibroblasts are refractory to Fas-mediated apoptosis and neutralization of autocrine transforming growth factor-beta1 can abrogate this resistance. American Journal of Pathology 157, 1661-1669CrossRefGoogle ScholarPubMed
132Tanaka, T. et al. (2002) Resistance to Fas-mediated apoptosis in human lung fibroblast. European Respiratory Journal 20, 359-368Google Scholar
133Kazufumi, M. et al. (1997) Expression of bcl-2 protein and APO-1 (Fas antigen) in the lung tissue from patients with idiopathic pulmonary fibrosis. Microscopy Research and Technique 38, 480-487Google Scholar
134Marcotte, R., Lacelle, C. and Wang, E. (2004) Senescent fibroblasts resist apoptosis by downregulating caspase-3. Mechanisms of Ageing and Development 125, 777-783Google Scholar
135Budinger, G.R. et al. (2006) Proapoptotic bid is required for pulmonary fibrosis. Proceedings of the National Academy of Sciences of the United States of America 103, 4604-4609Google Scholar
136Yamada, M. et al. (2007) Gene transfer of soluble transforming growth factor type II receptor by in vivo electroporation attenuates lung injury and fibrosis. Journal of Clinical Pathology 60, 916-920Google Scholar
137Bonner, J.C. (2004) Regulation of PDGF and its receptors in fibrotic diseases. Cytokine and Growth Factor Reviews 15, 255-273CrossRefGoogle ScholarPubMed
138Bonner, J.C. (2010) Mesenchymal cell survival in airway and interstitial pulmonary fibrosis. Fibrogenesis Tissue Repair 3, 15Google Scholar
139Shao, H., Yi, X.M. and Wells, A. (2008) Epidermal growth factor protects fibroblasts from apoptosis via PI3 kinase and Rac signaling pathways. Wound Repair and Regeneration 16, 551-558Google Scholar
140Moodley, Y.P. et al. (2003) Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs. American Journal of Respiratory Cell and Molecular Biology 29, 490-498Google Scholar
141Santiago, B. et al. (2004) Intracellular regulation of Fas-induced apoptosis in human fibroblasts by extracellular factors and cycloheximide. Journal of Immunology 172, 560-566Google Scholar
142White, E.S. et al. (2006) Negative regulation of myofibroblast differentiation by PTEN (Phosphatase and Tensin Homolog Deleted on chromosome 10). American Journal of Respiratory and Critical Care Medicine 173, 112-121Google Scholar
143Nho, R.S. et al. (2006) PTEN regulates fibroblast elimination during collagen matrix contraction. Journal of Biological Chemistry 281, 33291-33301Google Scholar
144Kulasekaran, P. et al. (2009) Endothelin-1 and transforming growth factor-beta1 independently induce fibroblast resistance to apoptosis via AKT activation. American Journal of Respiratory Cell and Molecular Biology 41, 484-493Google Scholar
145Chung, M.J. et al. (2007) Antiapoptotic effect of found in inflammatory zone (FIZZ)1 on mouse lung fibroblasts. Journal of Pathology 212, 180-187Google Scholar
146Bridges, R.S. et al. (2009) Gene expression profiling of pulmonary fibrosis identifies Twist1 as an antiapoptotic molecular “rectifier” of growth factor signaling. American Journal of Pathology 175, 2351-2361Google Scholar
147Nishimura, S.L. (2009) Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders. American Journal of Pathology 175, 1362-1370Google Scholar
148Farias, E. et al. (2005) Integrin alpha8beta1-fibronectin interactions promote cell survival via PI3 kinase pathway. Biochemical and Biophysical Research Communications 329, 305-311CrossRefGoogle ScholarPubMed
149Lin, F. et al. (2011) Fibronectin growth factor-binding domains are required for fibroblast survival. Journal of Investigative Dermatology 131, 84-98Google Scholar
150Hadden, H.L. and Henke, C.A. (2000) Induction of lung fibroblast apoptosis by soluble fibronectin peptides. American Journal of Respiratory and Critical Care Medicine 162, 1553-1560Google Scholar
151Horowitz, J.C. et al. (2007) Combinatorial activation of FAK and AKT by transforming growth factor-beta1 confers an anoikis-resistant phenotype to myofibroblasts. Cellular Signalling 19, 761-771Google Scholar
152Nho, R.S. et al. (2005) Role of integrin-linked kinase in regulating phosphorylation of Akt and fibroblast survival in type I collagen matrices through a beta1 integrin viability signaling pathway. Journal of Biological Chemistry 280, 26630-26639Google Scholar
153Janssen-Heininger, Y.M. et al. (2010) Regulation of apoptosis through cysteine oxidation: implications for fibrotic lung disease. Annals of the New York Academy of Sciences 1203, 23-28Google Scholar
154Tzouvelekis, A. et al. (2007) Comparative expression profiling in pulmonary fibrosis suggests a role of hypoxia-inducible factor-1alpha in disease pathogenesis. American Journal of Respiratory and Critical Care Medicine 176, 1108-1119Google Scholar
155Chilosi, M. et al. (2003) Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis. American Journal of Pathology 162, 1495-1502Google Scholar
156Pecina-Slaus, N. (2010) Wnt signal transduction pathway and apoptosis: a review. Cancer Cell International 10, 22Google Scholar
157Hueber, A.O. et al. (1994) Thy-1 triggers mouse thymocyte apoptosis through a bcl-2-resistant mechanism. Journal of Experimental Medicine 179, 785-796Google Scholar
158Morita, H. et al. (1996) Thy-1 antigen mediates apoptosis of rat glomerular cells in vitro and in vivo. Nephron 73, 293-298Google Scholar
159Kotaru, C. et al. (2006) Regional fibroblast heterogeneity in the lung: implications for remodeling. American Journal of Respiratory and Critical Care Medicine 173, 1208-1215Google Scholar
160Xie, X.-S. et al. (2010) LSKL, a peptide antagonist of thrombospondin-1, attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction. Archives of Pharmacal Research 33, 275-284Google Scholar
161Nakashima, T. et al. (2008) Suppressor of cytokine signaling 1 inhibits pulmonary inflammation and fibrosis. Journal of Allergy and Clinical Immunology 121, 1269-1276Google Scholar
162Moore, B.B. et al. (2001) Protection from pulmonary fibrosis in the absence of CCR2 signaling. Journal of Immunology 167, 4368-4377Google Scholar
163Cho, M.E. et al. (2007) Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clinical Journal of the American Society of Nephrology 2, 906-913Google Scholar
164Kakugawa, T. et al. (2004) Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis. European Respiratory Journal 24, 57-65Google Scholar
165Lasky, J. (2004) Pirfenidone. IDrugs 7, 166-172Google Scholar
166Noble, P.W. et al. (2011) Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 377, 1760-1769Google Scholar
167Douglass, A. et al. (2008) Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury. Journal of Hepatology 49, 88-98Google Scholar
168Vittal, R. et al. (2007) Effects of the protein kinase inhibitor, imatinib mesylate, on epithelial/mesenchymal phenotypes: implications for treatment of fibrotic diseases. Journal of Pharmacology and Experimental Therapeutics 321, 35-44Google Scholar
169Kisseleva, T. and Brenner, D.A. (2011) Is it the end of the line for the EMT? Hepatology 53, 1433-1435CrossRefGoogle ScholarPubMed
170Kinoshita, K. et al. (2007) Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats. Gut 56, 706-714Google Scholar
171Crosby, L.M. and Waters, C.M. (2010) Epithelial repair mechanisms in the lung. American Journal of Physiology. Lung Cellular and Molecular Physiology 298, L715-L731Google Scholar
172Nho, R. and Kahm, J. (2010) β1-Integrin-collagen interaction suppresses FoxO3a by the coordination of Akt and PP2A. Journal of Biological Chemistry 285, 14195-14209Google Scholar
173Wang, X.M. et al. (2006) Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis. Journal of Experimental Medicine 203, 2895-2906Google Scholar

Further reading, resources and contacts

Hinz, B. (2007) Formation and function of the myofibroblast during tissue repair. Journal of Investigative Dermatology 127, 526-537Google Scholar
Hinz, B. (2010) The myofibroblast: paradigm for a mechanically active cell. Journal of Biomechanics 43, 146-155CrossRefGoogle ScholarPubMed
Wipff, P.-J. et al. (2007) Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. Journal of Cell Biology 179, 1311-1323Google Scholar
Kisseleva, T. et al. (2011) Is it the end of the line for the EMT? Hepatology 53, 1433-1435 (Ref. 169).Google Scholar
A well-maintained website with excellent figures and movies, brief reviews, and helpful external links can be found at:http://www.cellmigration.org/.Google Scholar
Website of the American Society for Matrix Biology, with meeting announcements, resources and external links:http://www.asmb.net/.Google Scholar
Hinz, B. (2007) Formation and function of the myofibroblast during tissue repair. Journal of Investigative Dermatology 127, 526-537Google Scholar
Hinz, B. (2010) The myofibroblast: paradigm for a mechanically active cell. Journal of Biomechanics 43, 146-155CrossRefGoogle ScholarPubMed
Wipff, P.-J. et al. (2007) Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. Journal of Cell Biology 179, 1311-1323Google Scholar
Kisseleva, T. et al. (2011) Is it the end of the line for the EMT? Hepatology 53, 1433-1435 (Ref. 169).Google Scholar
A well-maintained website with excellent figures and movies, brief reviews, and helpful external links can be found at:http://www.cellmigration.org/.Google Scholar
Website of the American Society for Matrix Biology, with meeting announcements, resources and external links:http://www.asmb.net/.Google Scholar