Understanding the origin, activation and regulation of matrix-producing myofibroblasts for treatment of fibrotic disease

Journal of Pathology - Tập 231 Số 3 - Trang 273-289 - 2013
Rafael Kramann1,2,3,4, Derek P. DiRocco1,2,3, Benjamin D. Humphreys1,2,5
1Brigham and Women's Hospital, Boston, MA, USA
2Harvard Medical School, Boston, MA, USA
3RK and DPD contributed equally to this review.
4RWTH Aachen University, Division of Nephrology, Aachen, Germany
5Harvard Stem Cell Institute, Cambridge, MA, USA

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Humphreys, 2012, Targeting pericyte differentiation as a strategy to modulate kidney fibrosis in diabetic nephropathy, Semin Nephrol, 32, 463, 10.1016/j.semnephrol.2012.07.009

Ke, 2012, Hepatitis C virus and cellular stress response: implications to molecular pathogenesis of liver diseases, Viruses, 4, 2251, 10.3390/v4102251

Weber, 2013, Myofibroblast-mediated mechanisms of pathological remodelling of the heart, Nat Rev Cardiol, 10, 15, 10.1038/nrcardio.2012.158

Kong, 2013, The pathogenesis of cardiac fibrosis, Cell Mol Life Sci

Wynn, 2011, Integrating mechanisms of pulmonary fibrosis, J Exp Med, 208, 1339, 10.1084/jem.20110551

Duffield, 2013, Host responses in tissue repair and fibrosis, Annu Rev Pathol, 8:, 241, 10.1146/annurev-pathol-020712-163930

Otranto, 2012, The role of the myofibroblast in tumor stroma remodeling, Cell Adh Migr, 6, 203, 10.4161/cam.20377

Eyden, 2005, The myofibroblast a study of normal, reactive and neoplastic tissues, with an emphasis on ultrastructure. Part 2-tumours and tumour-like lesions, J Submicrosc Cytol Pathol, 37, 231

Hinz, 2010, The myofibroblast: paradigm for a mechanically active cell, J Biomech, 43, 146, 10.1016/j.jbiomech.2009.09.020

Follonier Castella, 2010, Regulation of myofibroblast activities: calcium pulls some strings behind the scene, Exp Cell Res, 316, 2390, 10.1016/j.yexcr.2010.04.033

Lin, 2008, Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney, Am J Pathol, 173, 1617, 10.2353/ajpath.2008.080433

Nakaya, 2013, EMT in developmental morphogenesis, Cancer Lett, 10.1016/j.canlet.2013.02.037

Kalluri, 2009, The basics of epithelial-mesenchymal transition, J Clin Invest, 119, 1420, 10.1172/JCI39104

Liu, 2004, Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention, J Am Soc Nephrol, 15, 1, 10.1097/01.ASN.0000106015.29070.E7

Humphreys, 2010, Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis, Am J Pathol, 176, 85, 10.2353/ajpath.2010.090517

Kida, 2011, Pivotal role of pericytes in kidney fibrosis, Clin Exp Pharmacol Physiol, 38, 467, 10.1111/j.1440-1681.2011.05531.x

Le Hir, 2005, Characterization of renal interstitial fibroblast-specific protein 1/S100A4-positive cells in healthy and inflamed rodent kidneys, Histochem Cell Biol, 123, 335, 10.1007/s00418-005-0788-z

Mlodzik, 1995, Ecto-5′-nucleotidase is expressed by pericytes and fibroblasts in the rat heart, Histochem Cell Biol, 103, 227, 10.1007/BF01454028

Kim, 2006, Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix, Proc Natl Acad Sci USA, 103, 13180, 10.1073/pnas.0605669103

Zeisberg, 2007, Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition, J Biol Chem, 282, 23337, 10.1074/jbc.M700194200

Rastaldi, 2002, Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies, Kidney Int, 62, 137, 10.1046/j.1523-1755.2002.00430.x

Zeisberg, 2003, BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury, Nat Med, 9, 964, 10.1038/nm888

Iwano, 2002, Evidence that fibroblasts derive from epithelium during tissue fibrosis, J Clin Invest, 110, 341, 10.1172/JCI0215518

Chu, 2011, Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis, Hepatology, 53, 1685, 10.1002/hep.24206

Rock, 2011, Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition, Proc Natl Acad Sci USA, 108, E1475, 10.1073/pnas.1117988108

Zeisberg, 2007, Endothelial-to-mesenchymal transition contributes to cardiac fibrosis, Nat Med, 13, 952, 10.1038/nm1613

Phua, 2013, Distinct sites of renal fibrosis in Crim1 mutant mice arise from multiple cellular origins, J Pathol, 229, 685, 10.1002/path.4155

Medici, 2010, Conversion of vascular endothelial cells into multipotent stem-like cells, Nat Med, 16, 1400, 10.1038/nm.2252

De Palma, 2005, Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors, Cancer Cell, 8, 211, 10.1016/j.ccr.2005.08.002

De Palma, 2003, Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells, Nat Med, 9, 789, 10.1038/nm871

Ning, 2011, Mesenchymal stem cell marker Stro-1 is a 75 kDa endothelial antigen, Biochem Biophys Res Commun, 413, 353, 10.1016/j.bbrc.2011.08.104

Tigges, 2012, A novel and simple method for culturing pericytes from mouse brain, Microvasc Res, 84, 74, 10.1016/j.mvr.2012.03.008

Gitlin, 1983, Culture of retinal capillary cells using selective growth media, Microvasc Res, 26, 74, 10.1016/0026-2862(83)90056-0

Russo, 2006, The bone marrow functionally contributes to liver fibrosis, Gastroenterology, 130, 1807, 10.1053/j.gastro.2006.01.036

Forbes, 2004, A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis, Gastroenterology, 126, 955, 10.1053/j.gastro.2004.02.025

Scholten, 2011, Migration of fibrocytes in fibrogenic liver injury, Am J Pathol, 179, 189, 10.1016/j.ajpath.2011.03.049

Kisseleva, 2011, Anti-fibrogenic strategies and the regression of fibrosis, Best Pract Res Clin Gastroenterol, 25, 305, 10.1016/j.bpg.2011.02.011

Moore, 2005, CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury, Am J Pathol, 166, 675, 10.1016/S0002-9440(10)62289-4

Moore, 2006, The role of CCL12 in the recruitment of fibrocytes and lung fibrosis, Am J Resp Cell Mol Biol, 35, 175, 10.1165/rcmb.2005-0239OC

Phillips, 2004, Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis, J Clin Invest, 114, 438, 10.1172/JCI200420997

Lebleu, 2013, Origin and function of myofibroblasts in kidney fibrosis, Nat Med, 19, 1047, 10.1038/nm.3218

Falkenham, 2013, Early fibroblast progenitor cell migration to the AngII-exposed myocardium is not CXCL12 or CCL2 dependent as previously thought, Am J Pathol, 183, 459, 10.1016/j.ajpath.2013.04.011

Frangogiannis, 2007, Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy, Circulation, 115, 584, 10.1161/CIRCULATIONAHA.106.646091

Haudek, 2006, Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice, Proc Natl Acad Sci USA, 103, 18284, 10.1073/pnas.0608799103

Mollmann, 2006, Bone marrow-derived cells contribute to infarct remodelling, Cardiovasc Res, 71, 661, 10.1016/j.cardiores.2006.06.013

et al. Gastroenterology 137

Kisseleva, 2006, Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis, J Hepatol, 45, 429, 10.1016/j.jhep.2006.04.014

Hashimoto, 2004, Bone marrow-derived progenitor cells in pulmonary fibrosis, J Clin Invest, 113, 243, 10.1172/JCI200418847

Roufosse, 2006, Bone marrow-derived cells do not contribute significantly to collagen I synthesis in a murine model of renal fibrosis, J Am Soc Nephrol, 17, 775, 10.1681/ASN.2005080795

Reich, 2013, Fibrocytes develop outside the kidney but contribute to renal fibrosis in a mouse model, Kidney Int, 84, 78, 10.1038/ki.2013.84

Picard, 2008, Origin of renal myofibroblasts in the model of unilateral ureter obstruction in the rat, Histochem Cell Biol, 130, 141, 10.1007/s00418-008-0433-8

Iwaisako, 2012, What's new in liver fibrosis? The origin of myofibroblasts in liver fibrosis, J Gastroenterol Hepatol, 27, 65, 10.1111/j.1440-1746.2011.07002.x

Gabbiani, 1996, The cellular derivation and the life span of the myofibroblast, Pathol Res Pract, 192, 708, 10.1016/S0344-0338(96)80092-6

Rajkumar, 2005, Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis, Arthritis Res Ther, 7, R1113, 10.1186/ar1790

Levinson, 2005, Foxd1-dependent signals control cellularity in the renal capsule a structure required for normal renal development, Development, 132, 529, 10.1242/dev.01604

Hatini, 1996, Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2, Genes Dev, 10, 1467, 10.1101/gad.10.12.1467

Grgic, 2012, The origin of interstitial myofibroblasts in chronic kidney disease, Pediatr Nephrol, 27, 183, 10.1007/s00467-011-1772-6

Goritz, 2011, A pericyte origin of spinal cord scar tissue, Science, 333, 238, 10.1126/science.1203165

Dulauroy, 2012, Lineage tracing and genetic ablation of ADAM12+ perivascular cells identify a major source of profibrotic cells during acute tissue injury, Nat Med, 18, 1262, 10.1038/nm.2848

Armulik, 2011, Pericytes: developmental, physiological, and pathological perspectives, problems, and promises, Dev Cell, 21, 193, 10.1016/j.devcel.2011.07.001

Crisan, 2009, Perivascular multipotent progenitor cells in human organs, Ann NY Acad Sci, 1176:, 118, 10.1111/j.1749-6632.2009.04967.x

Chen, 2011, Platelet-derived growth factor receptor signaling activates pericyte-myofibroblast transition in obstructive and post-ischemic kidney fibrosis, Kidney Int, 80, 1170, 10.1038/ki.2011.208

Lin, 2011, Targeting endothelium-pericyte crosstalk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis, Am J Pathol, 178, 911, 10.1016/j.ajpath.2010.10.012

Asada, 2011, Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice, J Clin Invest, 121, 3981, 10.1172/JCI57301

Seikrit, 2013, Biological responses to PDGF-AA versus PDGF-CC in renal fibroblasts, Nephrol Dial Transpl, 28, 889, 10.1093/ndt/gfs509

Yamate, 1996, Immunohistochemical study of rat renal interstitial fibrosis induced by repeated injection of cisplatin, with special reference to the kinetics of macrophages and myofibroblasts, Toxicol Pathol, 24, 199, 10.1177/019262339602400208

Degryse, 2010, Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis, Am J Physiol Lung Cell Mol Physiol, 299, L442, 10.1152/ajplung.00026.2010

Shi, 1998, Evidence of hepatocyte apoptosis in rat liver after the administration of carbon tetrachloride, Am J Pathol, 153, 515, 10.1016/S0002-9440(10)65594-0

Grgic, 2012, Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis, Kidney Int, 82, 172, 10.1038/ki.2012.20

Koesters, 2010, Tubular overexpression of transforming growth factor-β1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells, Am J Pathol, 177, 632, 10.2353/ajpath.2010.091012

Friedman, 2013, Therapy for fibrotic diseases: nearing the starting line, Sci Transl Med, 5, 10.1126/scitranslmed.3004700

Wick, 2013, The immunology of fibrosis, Annu Rev Immunol, 31:, 107, 10.1146/annurev-immunol-032712-095937

Zhang, 1993, Enhanced IL-1β and tumor necrosis factor-α release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure, J Immunol, 150, 4188, 10.4049/jimmunol.150.9.4188

Piguet, 1989, Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis, J Exp Med, 170, 655, 10.1084/jem.170.3.655

Tomita, 2006, Tumour necrosis factor-α signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice, Gut, 55, 415, 10.1136/gut.2005.071118

He, 2010, Inflammation and fibrosis during Chlamydia pneumoniae infection is regulated by IL-1 and the NLRP3/ASC inflammasome, J Immunol, 184, 5743, 10.4049/jimmunol.0903937

Vilaysane, 2010, The NLRP3 inflammasome promotes renal inflammation and contributes to CKD, J Am Soc Nephrol, 21, 1732, 10.1681/ASN.2010020143

Wilson, 2010, Bleomycin and IL-1β-mediated pulmonary fibrosis is IL-17A dependent, J Exp Med, 207, 535, 10.1084/jem.20092121

Feng, 2009, IL-17 induces myocardial fibrosis and enhances RANKL/OPG and MMP/TIMP signaling in isoproterenol-induced heart failure, Exp Mol Pathol, 87, 212, 10.1016/j.yexmp.2009.06.001

Foster, 2012, Interleukin (IL)-17/IL-22-producing T cells enriched within the liver of patients with chronic hepatitis C viral (HCV) infection, Dig Dis Sci, 57, 381, 10.1007/s10620-011-1997-z

Rosenbloom, 2013, Strategies for anti-fibrotic therapies, Biochim Biophys Acta, 1832, 1088, 10.1016/j.bbadis.2012.12.007

Gasse, 2011, IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis, PLoS One, 6, e23185, 10.1371/journal.pone.0023185

Nakashima, 2012, Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts, J Immunol, 188, 3573, 10.4049/jimmunol.1100591

Lo Re, 2010, IL-17A-producing γδT and Th17 lymphocytes mediate lung inflammation but not fibrosis in experimental silicosis, J Immunol, 184, 6367, 10.4049/jimmunol.0900459

Wynn, 2004, Fibrotic disease and the Th1/Th2 paradigm, Nat Rev Immunol, 4, 583, 10.1038/nri1412

Shi, 1997, Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses, Proc Natl Acad Sci USA, 94, 10663, 10.1073/pnas.94.20.10663

Furuie, 1997, Altered accessory cell function of alveolar macrophages a possible mechanism for induction of Th2 secretory profile in idiopathic pulmonary fibrosis, Eur Respir J, 10, 787, 10.1183/09031936.97.10040787

Mavalia, 1997, Type 2 helper T-cell predominance and high CD30 expression in systemic sclerosis, Am J Pathol, 151, 1751

Yoshizaki, 2010, Cell adhesion molecules regulate fibrotic process via Th1/Th2/Th17 cell balance in a bleomycin-induced scleroderma model, J Immunol, 185, 2502, 10.4049/jimmunol.0901778

Kolodsick, 2004, Protection from fluorescein isothiocyanate-induced fibrosis in IL-13-deficient, but not IL-4-deficient, mice results from impaired collagen synthesis by fibroblasts, J Immunol, 172, 4068, 10.4049/jimmunol.172.7.4068

Weng, 2009, The etiology of liver damage imparts cytokines transforming growth factor-β1 or interleukin-13 as driving forces in fibrogenesis, Hepatology, 50, 230, 10.1002/hep.22934

Shimamura, 2008, Novel role of IL-13 in fibrosis induced by nonalcoholic steatohepatitis and its amelioration by IL-13R-directed cytotoxin in a rat model, J Immunol, 181, 4656, 10.4049/jimmunol.181.7.4656

Han, 2011, Th2-like immune response in radiation-induced lung fibrosis, Oncol Rep, 26, 383

Chiaramonte, 2003, Regulation and function of the interleukin 13 receptor-α2 during a T helper cell type 2-dominant immune response, J Exp Med, 197, 687, 10.1084/jem.20020903

Duffield, 2005, Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair, J Clin Invest, 115, 56, 10.1172/JCI200522675

Duffield, 2005, Conditional ablation of macrophages halts progression of crescentic glomerulonephritis, Am J Pathol, 167, 1207, 10.1016/S0002-9440(10)61209-6

Castano, 2009, Serum amyloid P inhibits fibrosis through FcγR-dependent monocyte-macrophage regulation in vivo, Sci Transl Med, 1, 10.1126/scitranslmed.3000111

Mosser, 2008, Exploring the full spectrum of macrophage activation, Nat Rev Immunol, 8, 958, 10.1038/nri2448

Wynn, 2010, Macrophages: master regulators of inflammation and fibrosis, Semin Liver Dis, 30, 245, 10.1055/s-0030-1255354

Wahl, 1990, Macrophage production of TGFβ and regulation by TGFβ, Ann NY Acad Sci, 593:, 188, 10.1111/j.1749-6632.1990.tb16111.x

Henke, 1993, Macrophage production of basic fibroblast growth factor in the fibroproliferative disorder of alveolar fibrosis after lung injury, Am J Pathol, 143, 1189

Martinet, 1987, Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis, N Engl J Med, 317, 202, 10.1056/NEJM198707233170404

Prasse, 2006, A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18, Am J Respir Crit Care Med, 173, 781, 10.1164/rccm.200509-1518OC

Chen, 2013, Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats, Am J Physiol Renal Physiol, 304, F676, 10.1152/ajprenal.00507.2012

Spencer, 2010, Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation, Am J Physiol Endocrinol Metab, 299, E1016, 10.1152/ajpendo.00329.2010

Nishida, 2005, Adoptive transfer of macrophages ameliorates renal fibrosis in mice, Biochem Biophys Res Commun, 332, 11, 10.1016/j.bbrc.2005.04.083

Murai, 2009, Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis, Nat Immunol, 10, 1178, 10.1038/ni.1791

Strien, 2010, Anti-inflammatory effect by lentiviral-mediated overexpression of IL-10 or IL-1 receptor antagonist in rat glial cells and macrophages, Gene Ther, 17, 662, 10.1038/gt.2010.8

Ingham, 1998, Transducing Hedgehog: the story so far, EMBO J, 17, 3505, 10.1093/emboj/17.13.3505

Briscoe, 2013, The mechanisms of Hedgehog signalling and its roles in development and disease, Nat Rev Mol Cell Biol, 14, 416, 10.1038/nrm3598

Hu, 2006, GLI3-dependent transcriptional repression of Gli1, Gli2 and kidney patterning genes disrupts renal morphogenesis, Development, 133, 569, 10.1242/dev.02220

Yauch, 2008, A paracrine requirement for hedgehog signalling in cancer, Nature, 455, 406, 10.1038/nature07275

Shin, 2011, Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder, Nature, 472, 110, 10.1038/nature09851

Choi, 2011, The role of Hedgehog signaling in fibrogenic liver repair, Int J Biochem Cell Biol, 43, 238, 10.1016/j.biocel.2010.10.015

Michelotti, 2013, Smoothened is a master regulator of adult liver repair, J Clin Invest, 123, 2380

Stewart, 2003, Expression of the developmental Sonic hedgehog (Shh) signalling pathway is up-regulated in chronic lung fibrosis and the Shh receptor patched 1 is present in circulating T lymphocytes, J Pathol, 199, 488, 10.1002/path.1295

Fabian, 2012, Hedgehog-Gli pathway activation during kidney fibrosis, Am J Pathol, 180, 1441, 10.1016/j.ajpath.2011.12.039

Ding, 2012, Sonic hedgehog signaling mediates epithelial-mesenchymal communication and promotes renal fibrosis, J Am Soc Nephrol, 23, 801, 10.1681/ASN.2011060614

Sahebjam, 2012, The utility of hedgehog signaling pathway inhibition for cancer, Oncologist, 17, 1090, 10.1634/theoncologist.2011-0450

Jenkins, 2009, Hedgehog signalling: emerging evidence for non-canonical pathways, Cell Signal, 21, 1023, 10.1016/j.cellsig.2009.01.033

Floege, 2008, A new look at platelet-derived growth factor in renal disease, J Am Soc Nephrol, 19, 12, 10.1681/ASN.2007050532

Leask, 2010, Potential therapeutic targets for cardiac fibrosis: TGFβ, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation, Circ Res, 106, 1675, 10.1161/CIRCRESAHA.110.217737

Rajkumar, 2006, Platelet-derived growth factor-β receptor activation is essential for fibroblast and pericyte recruitment during cutaneous wound healing, Am J Pathol, 169, 2254, 10.2353/ajpath.2006.060196

Campanholle, 2013, Cellular mechanisms of tissue fibrosis. 3. Novel mechanisms of kidney fibrosis, Am J Physiol Cell Physiol, 304, C591, 10.1152/ajpcell.00414.2012

Zymek, 2006, The role of platelet-derived growth factor signaling in healing myocardial infarcts, J Am Coll Cardiol, 48, 2315, 10.1016/j.jacc.2006.07.060

Liao, 2010, Cardiac mast cells cause atrial fibrillation through PDGF-A-mediated fibrosis in pressure-overloaded mouse hearts, J Clin Invest, 120, 242, 10.1172/JCI39942

Lewis, 2005, Airway fibroblasts exhibit a synthetic phenotype in severe asthma, J Allergy Clin Immunol, 115, 534, 10.1016/j.jaci.2004.11.051

Mukherjee, 2013, Platelet derived growth factor-evoked Ca2+ wave and matrix gene expression through phospholipase C in human pulmonary fibroblast, Int J Biochem Cell Biol, 45, 1516, 10.1016/j.biocel.2013.04.018

Martin, 2013, Platelet-derived growth factor (PDGF)-C neutralization reveals differential roles of PDGF receptors in liver and kidney fibrosis, Am J Pathol, 182, 107, 10.1016/j.ajpath.2012.09.006

Huang, 2013, Blockade of KCa3.1 ameliorates renal fibrosis through the TGF-β1/Smad pathway in diabetic mice, Diabetes, 62, 2923, 10.2337/db13-0135

Yamamoto, 1993, Expression of transforming growth factor-β is elevated in human and experimental diabetic nephropathy, Proc Natl Acad Sci USA, 90, 1814, 10.1073/pnas.90.5.1814

Pohlers, 2007, Constitutive upregulation of the transforming growth factor-β pathway in rheumatoid arthritis synovial fibroblasts, Arthritis Res Ther, 9, R59, 10.1186/ar2217

Bujak, 2007, The role of TGF-β signaling in myocardial infarction and cardiac remodeling, Cardiovasc Res, 74, 184, 10.1016/j.cardiores.2006.10.002

Daniels, 2004, Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis, J Clin Invest, 114, 1308, 10.1172/JCI200419603

Pohlers, 2009, TGF-β and fibrosis in different organs-molecular pathway imprints, Biochim Biophys Acta, 1792, 746, 10.1016/j.bbadis.2009.06.004

Wipff, 2008, Integrins and the activation of latent transforming growth factor-β1-an intimate relationship, Eur J Cell Biol, 87, 601, 10.1016/j.ejcb.2008.01.012

Saharinen, 2000, Specific sequence motif of 8-Cys repeats of TGF-β binding proteins, LTBPs, creates a hydrophobic interaction surface for binding of small latent TGF-β, Mol Biol Cell, 11, 2691, 10.1091/mbc.11.8.2691

Yu, 2000, Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-β and promotes tumor invasion and angiogenesis, Genes Dev, 14, 163, 10.1101/gad.14.2.163

Poczatek, 2000, Glucose stimulation of transforming growth factor-β bioactivity in mesangial cells is mediated by thrombospondin-1, Am J Pathol, 157, 1353, 10.1016/S0002-9440(10)64649-4

Massague, 2000, How cells read TGF-β signals, Nat Rev Mol Cell Biol, 1, 169, 10.1038/35043051

Wahl, 1993, Reversal of acute and chronic synovial inflammation by anti-transforming growth factor-β, J Exp Med, 177, 225, 10.1084/jem.177.1.225

Ledbetter, 2000, Renal fibrosis in mice treated with human recombinant transforming growth factor-β2, Kidney Int, 58, 2367, 10.1046/j.1523-1755.2000.00420.x

Border, 1990, Suppression of experimental glomerulonephritis by antiserum against transforming growth factor-β1, Nature, 346, 371, 10.1038/346371a0

Sato, 2003, Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction, J Clin Invest, 112, 1486, 10.1172/JCI200319270

Inazaki, 2004, Kidney Int, 66, 597, 10.1111/j.1523-1755.2004.00779.x

Denton, 2007, Recombinant human anti-transforming growth factor-β1 antibody therapy in systemic sclerosis a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192, Arthritis Rheum, 56, 323, 10.1002/art.22289

Beyer, 2013, Tyrosine kinase signaling in fibrotic disorders: Translation of basic research to human disease, Biochim Biophys Acta, 1832, 897, 10.1016/j.bbadis.2012.06.008

Baselga, 2009, Novel anticancer targets: revisiting ERBB2 and discovering ERBB3, Nat Rev Cancer, 9, 463, 10.1038/nrc2656

Yarden, 2001, Untangling the ErbB signalling network, Nat Rev Mol Cell Biol, 2, 127, 10.1038/35052073

Harris, 2003, EGF receptor ligands, Exp Cell Res, 284, 2, 10.1016/S0014-4827(02)00105-2

Blaine, 2009, Epidermal growth factor receptor regulates pancreatic fibrosis, Am J Physiol Gastrointest Liver Physiol, 297, G434, 10.1152/ajpgi.00152.2009

Pang, 2010, A novel STAT3 inhibitor, S3I-201, attenuates renal interstitial fibroblast activation and interstitial fibrosis in obstructive nephropathy, Kidney Int, 78, 257, 10.1038/ki.2010.154

Terzi, 2000, Targeted expression of a dominant-negative EGF-R in the kidney reduces tubulo-interstitial lesions after renal injury, J Clin Invest, 106, 225, 10.1172/JCI8315

Liu, 2012, Genetic or pharmacologic blockade of EGFR inhibits renal fibrosis, J Am Soc Nephrol, 23, 854, 10.1681/ASN.2011050493

Tang, 2013, Sustained activation of EGFR triggers renal fibrogenesis after acute kidney injury, Am J Pathol, 183, 160, 10.1016/j.ajpath.2013.04.005

Chen, 2012, EGFR signaling promotes TGFβ-dependent renal fibrosis, J Am Soc Nephrol, 23, 215, 10.1681/ASN.2011070645

Liu, 1996, Up-regulated expression of transforming growth factor-α in the bronchiolar-alveolar duct regions of asbestos-exposed rats, Am J Pathol, 149, 205

Madtes, 1994, Expression of transforming growth factor-α and epidermal growth factor receptor is increased following bleomycin-induced lung injury in rats, Am J Respir Cell Mol Biol, 11, 540, 10.1165/ajrcmb.11.5.7524566

Hardie, 2004, Conditional expression of transforming growth factor-α in adult mouse lung causes pulmonary fibrosis, Am J Physiol Lung Cell Mol Physiol, 286, L741, 10.1152/ajplung.00208.2003

Ishii, 2006, Gefitinib prevents bleomycin-induced lung fibrosis in mice, Am J Respir Crit Care Med, 174, 550, 10.1164/rccm.200509-1534OC

Hardie, 2008, EGF receptor tyrosine kinase inhibitors diminish transforming growth factor-α-induced pulmonary fibrosis, Am J Physiol Lung Cell Mol Physiol, 294, L1217, 10.1152/ajplung.00020.2008

Suzuki, 2003, Epidermal growth factor receptor tyrosine kinase inhibition augments a murine model of pulmonary fibrosis, Cancer Res, 63, 5054

Fukumoto, 2010, Amphiregulin attenuates bleomycin-induced pneumopathy in mice, Am J Physiol Lung Cell Mol Physiol, 298, L131, 10.1152/ajplung.90576.2008

Kular, 2011, The CCN family a new class of inflammation modulators?, Biochimie, 93, 377, 10.1016/j.biochi.2010.11.010

Hinz, 2012, Recent developments in myofibroblast biology: paradigms for connective tissue remodeling, Am J Pathol, 180, 1340, 10.1016/j.ajpath.2012.02.004

Kennedy, 2007, CCN2 is necessary for the function of mouse embryonic fibroblasts, Exp Cell Res, 313, 952, 10.1016/j.yexcr.2006.12.006

Ponticos, 2009, Pivotal role of connective tissue growth factor in lung fibrosis: MAPK-dependent transcriptional activation of type I collagen, Arthritis Rheum, 60, 2142, 10.1002/art.24620

Huang, 2012, Regulation of hepatic stellate cells by connective tissue growth factor, Front Biosci, 17:, 2495, 10.2741/4067

Ren, 2013, LRP-6 is a coreceptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK-1, Proc Natl Acad Sci USA, 110, 1440, 10.1073/pnas.1211179110

Angers, 2009, Proximal events in Wnt signal transduction, Nat Rev Mol Cell Biol, 10, 468, 10.1038/nrm2717

Clevers, 2006, Wnt/β-catenin signaling in development and disease, Cell, 127, 469, 10.1016/j.cell.2006.10.018

Cheon, 2002, β-Catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and causes aggressive fibromatosis and hyperplastic cutaneous wounds, Proc Natl Acad Sci USA, 99, 6973, 10.1073/pnas.102657399

Lam, 2011, β-Catenin signaling a novel mediator of fibrosis and potential therapeutic target, Curr Opin Rheumatol, 23, 562, 10.1097/BOR.0b013e32834b3309

Beyer, 2012, β-Catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis, Ann Rheum Dis, 71, 761, 10.1136/annrheumdis-2011-200568

Beyer, 2013, Blockade of canonical Wnt signalling ameliorates experimental dermal fibrosis, Ann Rheum Dis, 72, 1255, 10.1136/annrheumdis-2012-202544

Akhmetshina, 2012, Activation of canonical Wnt signalling is required for TGFβ-mediated fibrosis, Nat Commun, 3:, 735, 10.1038/ncomms1734

Brack, 2007, Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis, Science, 317, 807, 10.1126/science.1144090

Lam, 2011, Nuclear β-catenin is increased in systemic sclerosis pulmonary fibrosis and promotes lung fibroblast migration and proliferation, Am J Respir Cell Mol Biol, 45, 915, 10.1165/rcmb.2010-0113OC

Chilosi, 2003, Aberrant Wnt/β-catenin pathway activation in idiopathic pulmonary fibrosis, Am J Pathol, 162, 1495, 10.1016/S0002-9440(10)64282-4

Hao, 2011, Targeted inhibition of β-catenin/CBP signaling ameliorates renal interstitial fibrosis, J Am Soc Nephrol, 22, 1642, 10.1681/ASN.2010101079

Surendran, 2002, A role for Wnt-4 in renal fibrosis, Am J Physiol Renal Physiol, 282, F431, 10.1152/ajprenal.0009.2001

Surendran, 2004, Matrilysin (MMP-7) expression in renal tubular damage: association with Wnt4, Kidney Int, 65, 2212, 10.1111/j.1523-1755.2004.00641.x

Dirocco DP Kobayashi A Taketo MM et al. β J Am Soc Nephrol 2013 24 9 : 1399 1412

Fortini, 2009, Notch signaling: the core pathway and its posttranslational regulation, Dev Cell, 16, 633, 10.1016/j.devcel.2009.03.010

Borggrefe, 2012, Fine-tuning of the intracellular canonical Notch signaling pathway, Cell Cycle, 11, 264, 10.4161/cc.11.2.18995

Morrissey, 2002, Transforming growth factor-β induces renal epithelial Jagged-1 expression in fibrotic disease, J Am Soc Nephrol, 13, 1499, 10.1097/01.ASN.0000017905.77985.4A

Bielesz, 2010, Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans, J Clin Invest, 120, 4040, 10.1172/JCI43025

Djudjaj, 2012, Notch-3 receptor activation drives inflammation and fibrosis following tubulointerstitial kidney injury, J Pathol, 228, 286, 10.1002/path.4076

Dees, 2011, Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis, Ann Rheum Dis, 70, 1304, 10.1136/ard.2010.134742

Liu, 2009, Notch1 signaling in FIZZ1 induction of myofibroblast differentiation, Am J Pathol, 174, 1745, 10.2353/ajpath.2009.080618

Spee, 2010, Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signalling, Gut, 59, 247, 10.1136/gut.2009.188367

Xie, 2013, Cross-talk between notch and hedgehog regulates hepatic stellate cell fate, Hepatology, 10.1002/hep.26511