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Inflammation-Independent Mechanisms of Intestinal Fibrosis: The Role of the Extracellular Matrix

  • Debby Laukens
Chapter

Abstract

Current therapies controlling inflammation in patients with Crohn’s disease do not modify natural disease progression to stenosis, suggesting that the molecular mechanisms contributing to intestinal fibrosis occur partly independent from inflammation. This may be explained by auto-propagation of fibrosis, accomplished by components of the interstitial, non-cellular environment referred to as the extracellular matrix (ECM). Aside from its function in maintaining tissue integrity, the ECM is a highly dynamic structure that closely communicates with cells, including with those that produce ECM components. Interaction of fibroblasts with the ECM through multi-protein focal adhesions orchestrates a variety of processes including proliferation, migration and activation. In particular, the mechanical properties of the ECM, determined by the degree of ‘stiffness’ which is typically increased in the stenotic bowel, induces a variety of pro-fibrotic signaling cascades in fibroblasts. Although the mechanical cues translating into the activation of these cells have only begun to be unraveled, mechanotransduction in fibroblasts should be considered as an important inflammation-independent contributor to intestinal fibrosis. In addition, the ECM is a reservoir of growth factors and a source of ‘danger signals’ that can trigger pro-fibrotic responses in the rigid ECM. This chapter provides an overview of the components of the intestinal ECM, the interaction with fibroblasts, and the inflammation-independent mechanisms contributing to fibrosis including mechanotransduction of fibroblasts and mechanical activation of the ECM. Finally, the potential therapeutic targets in these pathways to tackle fibrogenesis in the intestine are discussed.

Keywords

Mechanotransduction Integrins Focal adhesions Extracellular matrix stiffness Smad signaling and Rho kinases 

References

  1. 1.
    Gayer CP, Basson MD. The effects of mechanical forces on intestinal physiology and pathology. Cell Signal. 2009;21(8):1237–44.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Bosman FT, Stamenkovic I. Functional structure and composition of the extracellular matrix. J Pathol. 2003;200(4):423–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Bateman JF, Boot-Handford RP, Lamande SR. Genetic diseases of connective tissues: cellular and extracellular effects of ECM mutations. Nat Rev Genet. 2009;10(3):173–83.CrossRefPubMedGoogle Scholar
  4. 4.
    Rozario T, DeSimone DW. The extracellular matrix in development and morphogenesis: a dynamic view. Dev Biol. 2010;341(1):126–40.CrossRefPubMedGoogle Scholar
  5. 5.
    Shimshoni E, et al. ECM remodelling in IBD: innocent bystander or partner in crime? The emerging role of extracellular molecular events in sustaining intestinal inflammation. Gut. 2015;64(3):367–72.CrossRefPubMedGoogle Scholar
  6. 6.
    Kedinger M, et al. Intestinal epithelial-mesenchymal cell interactions. Ann N Y Acad Sci. 1998;859:1–17.CrossRefPubMedGoogle Scholar
  7. 7.
    Naba A, et al. The matrisome: in silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices. Mol Cell Proteomics. 2012;11(4):M111.014647.CrossRefPubMedGoogle Scholar
  8. 8.
    Ricard-Blum S. The collagen family. Cold Spring Harb Perspect Biol. 2011;3(1):a004978.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Mouw JK, Ou G, Weaver VM. Extracellular matrix assembly: a multiscale deconstruction. Nat Rev Mol Cell Biol. 2014;15(12):771–85.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Graham MF, et al. Collagen content and types in the intestinal strictures of Crohn’s disease. Gastroenterology. 1988;94(2):257–65.CrossRefPubMedGoogle Scholar
  11. 11.
    Shelley-Fraser G, et al. The connective tissue changes of Crohn’s disease. Histopathology. 2012;60(7):1034–44.CrossRefPubMedGoogle Scholar
  12. 12.
    Johnson LA, et al. Matrix stiffness corresponding to strictured bowel induces a fibrogenic response in human colonic fibroblasts. Inflamm Bowel Dis. 2013;19(5):891–903.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Esko JD, Kimata K, Lindahl U. Proteoglycans and sulfated glycosaminoglycans. In: Varki A, et al., editors. Essentials of glycobiology. New York: Cold Spring Harbor; 2009.Google Scholar
  14. 14.
    Jarvinen TA, Prince S. Decorin: a growth factor antagonist for tumor growth inhibition. Biomed Res Int. 2015;2015:654765.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Couchman JR. Transmembrane signaling proteoglycans. Annu Rev Cell Dev Biol. 2010;26:89–114.CrossRefPubMedGoogle Scholar
  16. 16.
    Herum KM, et al. The soft- and hard-heartedness of cardiac fibroblasts: mechanotransduction signaling pathways in fibrosis of the heart. J Clin Med. 2017;6(5):E53.CrossRefPubMedGoogle Scholar
  17. 17.
    Hynes WL, Walton SL. Hyaluronidases of Gram-positive bacteria. FEMS Microbiol Lett. 2000;183(2):201–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Spiro RG. Glycoproteins: structure, metabolism and biology. N Engl J Med. 1963;269:616–21.CrossRefPubMedGoogle Scholar
  19. 19.
    Bouatrouss Y, et al. Altered expression of laminins in Crohn’s disease small intestinal mucosa. Am J Pathol. 2000;156(1):45–50.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Serini G, et al. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1. J Cell Biol. 1998;142(3):873–81.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Brenmoehl J, et al. Evidence for a differential expression of fibronectin splice forms ED-A and ED-B in Crohn’s disease (CD) mucosa. Int J Colorectal Dis. 2007;22(6):611–23.CrossRefPubMedGoogle Scholar
  22. 22.
    Zemskov EA, et al. The role of tissue transglutaminase in cell-matrix interactions. Front Biosci. 2006;11:1057–76.CrossRefPubMedGoogle Scholar
  23. 23.
    Morgan MR, Humphries MJ, Bass MD. Synergistic control of cell adhesion by integrins and syndecans. Nat Rev Mol Cell Biol. 2007;8(12):957–69.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002;110(6):673–87.CrossRefGoogle Scholar
  25. 25.
    Zaidel-Bar R, et al. Functional atlas of the integrin adhesome. Nat Cell Biol. 2007;9(8):858–67.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Schiller HB, et al. Beta1- and alphav-class integrins cooperate to regulate myosin II during rigidity sensing of fibronectin-based microenvironments. Nat Cell Biol. 2013;15(6):625–36.CrossRefPubMedGoogle Scholar
  27. 27.
    Ierardi E, et al. Altered molecular pattern of mucosal healing in Crohn’s disease fibrotic stenosis. World J Gastrointest Pathophysiol. 2013;4(3):53–8.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Floer M, et al. Enoxaparin improves the course of dextran sodium sulfate-induced colitis in syndecan-1-deficient mice. Am J Pathol. 2010;176(1):146–57.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Akimov SS, et al. Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin. J Cell Biol. 2000;148(4):825–38.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Hinz B. The myofibroblast: paradigm for a mechanically active cell. J Biomech. 2010;43(1):146–55.CrossRefPubMedGoogle Scholar
  31. 31.
    Gabbiani G, Ryan GB, Majne G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia. 1971;27(5):549–50.CrossRefPubMedGoogle Scholar
  32. 32.
    Tomasek JJ, et al. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3(5):349–63.CrossRefPubMedGoogle Scholar
  33. 33.
    Hinz B, et al. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am J Pathol. 2001;159(3):1009–20.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Parker MW, et al. Fibrotic extracellular matrix activates a profibrotic positive feedback loop. J Clin Invest. 2014;124(4):1622–35.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Georges PC, et al. Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. Am J Physiol Gastrointest Liver Physiol. 2007;293(6):G1147–54.CrossRefPubMedGoogle Scholar
  36. 36.
    Stephens P, et al. Crosslinking and G-protein functions of transglutaminase 2 contribute differentially to fibroblast wound healing responses. J Cell Sci. 2004;117(Pt 15):3389–403.CrossRefPubMedGoogle Scholar
  37. 37.
    van der Slot AJ, et al. Elevated formation of pyridinoline cross-links by profibrotic cytokines is associated with enhanced lysyl hydroxylase 2b levels. Biochim Biophys Acta. 2005;1741(1-2):95–102.CrossRefPubMedGoogle Scholar
  38. 38.
    Yang J, et al. Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment. Nat Commun. 2016;7:13710.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Rivera E, et al. Molecular profiling of a rat model of colitis: validation of known inflammatory genes and identification of novel disease-associated targets. Inflamm Bowel Dis. 2006;12(10):950–66.CrossRefPubMedGoogle Scholar
  40. 40.
    Mambetsariev I, et al. Stiffness-activated GEF-H1 expression exacerbates LPS-induced lung inflammation. PLoS One. 2014;9(4):e92670.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kim K, et al. Noninvasive ultrasound elasticity imaging (UEI) of Crohn’s disease: animal model. Ultrasound Med Biol. 2008;34(6):902–12.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Stidham RW, et al. Ultrasound elasticity imaging for detecting intestinal fibrosis and inflammation in rats and humans with Crohn’s disease. Gastroenterology. 2011;141(3):819–826 e1.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Rault I, et al. Evaluation of different chemical methods for cross-linking collagen gel, films and sponges. J Mater Sci Mater Med. 1996;7(4):215–21.CrossRefGoogle Scholar
  44. 44.
    Syedain ZH, et al. Controlled compaction with ruthenium-catalyzed photochemical cross-linking of fibrin-based engineered connective tissue. Biomaterials. 2009;30(35):6695–701.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Badylak SF, et al. The use of xenogeneic small intestinal submucosa as a biomaterial for Achilles tendon repair in a dog model. J Biomed Mater Res. 1995;29(8):977–85.CrossRefPubMedGoogle Scholar
  46. 46.
    Lo CM, et al. Cell movement is guided by the rigidity of the substrate. Biophys J. 2000;79(1):144–52.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Goffin JM, et al. Focal adhesion size controls tension-dependent recruitment of alpha-smooth muscle actin to stress fibers. J Cell Biol. 2006;172(2):259–68.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Trappmann B, Chen CS. How cells sense extracellular matrix stiffness: a material’s perspective. Curr Opin Biotechnol. 2013;24(5):948–53.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Bershadsky A, Kozlov M, Geiger B. Adhesion-mediated mechanosensitivity: a time to experiment, and a time to theorize. Curr Opin Cell Biol. 2006;18(5):472–81.CrossRefPubMedGoogle Scholar
  50. 50.
    Discher DE, Janmey P, Wang YL. Tissue cells feel and respond to the stiffness of their substrate. Science. 2005;310(5751):1139–43.CrossRefGoogle Scholar
  51. 51.
    Wang N, et al. Cell prestress. I. Stiffness and prestress are closely associated in adherent contractile cells. Am J Physiol Cell Physiol. 2002;282(3):C606–16.CrossRefPubMedGoogle Scholar
  52. 52.
    Hinz B, et al. Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol Biol Cell. 2001;12(9):2730–41.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Sullivan KM, et al. A model of scarless human fetal wound repair is deficient in transforming growth factor beta. J Pediatr Surg. 1995;30(2):198–202; discussion 202-3.CrossRefPubMedGoogle Scholar
  54. 54.
    Kim SJ, et al. Autoinduction of transforming growth factor beta 1 is mediated by the AP-1 complex. Mol Cell Biol. 1990;10(4):1492–7.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Xia H, et al. Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway. J Biol Chem. 2004;279(31):33024–34.CrossRefPubMedGoogle Scholar
  56. 56.
    Zhang HY, Phan SH. Inhibition of myofibroblast apoptosis by transforming growth factor beta(1). Am J Respir Cell Mol Biol. 1999;21(6):658–65.CrossRefPubMedGoogle Scholar
  57. 57.
    Holvoet T, et al. Treatment of intestinal fibrosis in experimental inflammatory bowel disease by the pleiotropic actions of a local Rho kinase inhibitor. Gastroenterology. 2017;153(4):1054–67.CrossRefPubMedGoogle Scholar
  58. 58.
    Miyazono K, Ichijo H, Heldin CH. Transforming growth factor-beta: latent forms, binding proteins and receptors. Growth Factors. 1993;8(1):11–22.CrossRefPubMedGoogle Scholar
  59. 59.
    Henderson NC, et al. Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med. 2013;19(12):1617–24.CrossRefPubMedGoogle Scholar
  60. 60.
    Khalil N. TGF-beta: from latent to active. Microbes Infect. 1999;1(15):1255–63.CrossRefPubMedGoogle Scholar
  61. 61.
    Wipff PJ, et al. Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol. 2007;179(6):1311–23.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Verrecchia F, Chu ML, Mauviel A. Identification of novel TGF-beta/Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem. 2001;276(20):17058–62.CrossRefPubMedGoogle Scholar
  63. 63.
    Maeda T, et al. Conversion of mechanical force into TGF-beta-mediated biochemical signals. Curr Biol. 2011;21(11):933–41.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Grafe I, et al. Excessive transforming growth factor-beta signaling is a common mechanism in osteogenesis imperfecta. Nat Med. 2014;20(6):670–5.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Otte JM, Rosenberg IM, Podolsky DK. Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology. 2003;124(7):1866–78.CrossRefPubMedGoogle Scholar
  66. 66.
    Scheibner KA, et al. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol. 2006;177(2):1272–81.CrossRefPubMedGoogle Scholar
  67. 67.
    Soroosh A, et al. Crohn’s disease fibroblasts overproduce the novel protein KIAA1199 to create proinflammatory hyaluronan fragments. Cell Mol Gastroenterol Hepatol. 2016;2(3):358–368 e4.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Kessler S, et al. Hyaluronan (HA) deposition precedes and promotes leukocyte recruitment in intestinal inflammation. Clin Transl Sci. 2008;1(1):57–61.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Kelsh R, et al. Regulation of the innate immune response by fibronectin: synergism between the III-1 and EDA domains. PLoS One. 2014;9(7):e102974.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Cosnes J, et al. Impact of the increasing use of immunosuppressants in Crohn’s disease on the need for intestinal surgery. Gut. 2005;54(2):237–41.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Louis E, et al. Behaviour of Crohn’s disease according to the Vienna classification: changing pattern over the course of the disease. Gut. 2001;49(6):777–82.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Johnson LA, et al. Intestinal fibrosis is reduced by early elimination of inflammation in a mouse model of IBD: impact of a “Top-Down” approach to intestinal fibrosis in mice. Inflamm Bowel Dis. 2012;18(3):460–71.CrossRefPubMedGoogle Scholar
  73. 73.
    Seif-Naraghi SB, et al. Safety and efficacy of an injectable extracellular matrix hydrogel for treating myocardial infarction. Sci Transl Med. 2013;5(173):173ra25.CrossRefPubMedGoogle Scholar
  74. 74.
    Enemchukwu NO, et al. Synthetic matrices reveal contributions of ECM biophysical and biochemical properties to epithelial morphogenesis. J Cell Biol. 2016;212(1):113–24.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Wassenaar JW, et al. Evidence for mechanisms underlying the functional benefits of a myocardial matrix hydrogel for post-MI treatment. J Am Coll Cardiol. 2016;67(9):1074–86.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Yoshizumi T, et al. Timing effect of intramyocardial hydrogel injection for positively impacting left ventricular remodeling after myocardial infarction. Biomaterials. 2016;83:182–93.CrossRefPubMedGoogle Scholar
  77. 77.
    Barry-Hamilton V, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 2010;16(9):1009–17.CrossRefPubMedGoogle Scholar
  78. 78.
    Johnson TS, et al. Transglutaminase inhibition reduces fibrosis and preserves function in experimental chronic kidney disease. J Am Soc Nephrol. 2007;18(12):3078–88.CrossRefPubMedGoogle Scholar
  79. 79.
    Holzer LA, Holzer G. Injectable collagenase clostridium histolyticum for Dupuytren’s contracture. N Engl J Med. 2009;361(26):2579; author reply 2579-80.PubMedGoogle Scholar
  80. 80.
    McKleroy W, Lee TH, Atabai K. Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis. Am J Physiol Lung Cell Mol Physiol. 2013;304(11):L709–21.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Hill LJ, Ahmed Z, Logan A. Decorin treatment for reversing trabecular meshwork fibrosis in open-angle glaucoma. Neural Regen Res. 2016;11(6):922–3.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Diebold RJ, et al. Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated. Proc Natl Acad Sci U S A. 1995;92(26):12215–9.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Monteleone G, et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn’s disease. N Engl J Med. 2015;372(12):1104–13.CrossRefPubMedGoogle Scholar
  84. 84.
    Patsenker E, et al. Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis. Hepatology. 2009;50(5):1501–11.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Lo DJ, et al. Inhibition of alphavbeta6 promotes acute renal allograft rejection in nonhuman primates. Am J Transplant. 2013;13(12):3085–93.CrossRefPubMedGoogle Scholar
  86. 86.
    Targan SR, et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology. 2007;132(5):1672–83.CrossRefPubMedGoogle Scholar
  87. 87.
    Johnson LA, et al. Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF-beta-induced fibrogenesis in human colonic myofibroblasts. Inflamm Bowel Dis. 2014;20(1):154–65.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Fan GP, et al. Pharmacological inhibition of focal adhesion kinase attenuates cardiac fibrosis in mice cardiac fibroblast and post-myocardial-infarction models. Cell Physiol Biochem. 2015;37(2):515–26.CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Ghent UniversityGhentBelgium

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