Cell and Tissue Research

, Volume 365, Issue 3, pp 495–506 | Cite as

Epithelial-mesenchymal transition in tissue repair and fibrosis

  • Rivka C. Stone
  • Irena Pastar
  • Nkemcho Ojeh
  • Vivien Chen
  • Sophia Liu
  • Karen I. Garzon
  • Marjana Tomic-Canic
Review

Abstract

The epithelial-mesenchymal transition (EMT) describes the global process by which stationary epithelial cells undergo phenotypic changes, including the loss of cell-cell adhesion and apical-basal polarity, and acquire mesenchymal characteristics that confer migratory capacity. EMT and its converse, MET (mesenchymal-epithelial transition), are integral stages of many physiologic processes and, as such, are tightly coordinated by a host of molecular regulators. Converging lines of evidence have identified EMT as a component of cutaneous wound healing, during which otherwise stationary keratinocytes (the resident skin epithelial cells) migrate across the wound bed to restore the epidermal barrier. Moreover, EMT plays a role in the development of scarring and fibrosis, as the matrix-producing myofibroblasts arise from cells of the epithelial lineage in response to injury but are pathologically sustained instead of undergoing MET or apoptosis. In this review, we summarize the role of EMT in physiologic repair and pathologic fibrosis of tissues and organs. We conclude that further investigation into the contribution of EMT to the faulty repair of fibrotic wounds might identify components of EMT signaling as common therapeutic targets for impaired healing in many tissues.

Graphical Abstract

Model for injury-triggered EMT activation in physiologic wound repair (left) and fibrotic wound healing (right)

Keywords

Epithelial-mesenchymal transition Wound healing Fibrosis Keratinocytes Dermal fibroblasts 

References

  1. Abe R, Donnelly SC, Peng T, Bucala R, Metz CN (2001) Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 166:7556–7562PubMedCrossRefGoogle Scholar
  2. Aden N, Nuttall A, Shiwen X, de Winter P, Leask A, Black CM, Denton CP, Abraham DJ, Stratton RJ (2010) Epithelial cells promote fibroblast activation via IL-1alpha in systemic sclerosis. J Invest Dermatol 130:2191–2200PubMedCrossRefGoogle Scholar
  3. Ahmed N, Maines-Bandiera S, Quinn MA, Unger WG, Dedhar S, Auersperg N (2006) Molecular pathways regulating EGF-induced epithelio-mesenchymal transition in human ovarian surface epithelium. Am J Physiol Cell Physiol 290:C1532–C1542PubMedCrossRefGoogle Scholar
  4. Akhurst RJ, Derynck R (2001) TGF-beta signaling in cancer—a double-edged sword. Trends Cell Biol 11:S44–S51PubMedGoogle Scholar
  5. Arnoux V, Come C, Kusewitt D, Hudson L, Savagner P (2005) Cutaneous wound reepithelialization: a partial and reversible EMT. In: Savagner P (ed) Rise and fall of epithelial phenotype: concepts of epithelial-mesenchymal transition. Springer, Berlin, pp 111–134CrossRefGoogle Scholar
  6. Arnoux V, Nassour M, L’Helgoualc’h A, Hipskind RA, Savagner P (2008) Erk5 controls Slug expression and keratinocyte activation during wound healing. Mol Biol Cell 19:4738–4749PubMedPubMedCentralCrossRefGoogle Scholar
  7. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M (2008) Growth factors and cytokines in wound healing. Wound Repair Regen 16:585–601CrossRefPubMedGoogle Scholar
  8. Barrientos S, Brem H, Stojadinovic O, Tomic-Canic M (2014) Clinical application of growth factors and cytokines in wound healing. Wound Repair Regen 22:569–578PubMedPubMedCentralCrossRefGoogle Scholar
  9. Baum CL, Arpey CJ (2005) Normal cutaneous wound healing: clinical correlation with cellular and molecular events. Dermatol Surg 31:674–686. discussion 686PubMedCrossRefGoogle Scholar
  10. Billottet C, Tuefferd M, Gentien D, Rapinat A, Thiery JP, Broet P, Jouanneau J (2008) Modulation of several waves of gene expression during FGF-1 induced epithelial-mesenchymal transition of carcinoma cells. J Cell Biochem 104:826–839PubMedCrossRefGoogle Scholar
  11. Border WA, Noble NA (1994) Transforming growth factor beta in tissue fibrosis. N Engl J Med 331:1286–1292PubMedCrossRefGoogle Scholar
  12. Camenisch TD, Molin DG, Person A, Runyan RB, Gittenberger-de Groot AC, McDonald JA, Klewer SE (2002) Temporal and distinct TGFbeta ligand requirements during mouse and avian endocardial cushion morphogenesis. Dev Biol 248:170–181PubMedCrossRefGoogle Scholar
  13. Carretero M, Escamez MJ, Garcia M, Duarte B, Holguin A, Retamosa L, Jorcano JL, Rio MD, Larcher F (2008) In vitro and in vivo wound healing-promoting activities of human cathelicidin LL-37. J Invest Dermatol 128:223–236CrossRefPubMedGoogle Scholar
  14. Castilho RM, Squarize CH, Gutkind JS (2013) Exploiting PI3K/mTOR signaling to accelerate epithelial wound healing. Oral Dis 19:551–558PubMedPubMedCentralCrossRefGoogle Scholar
  15. Chapman HA (2011) Epithelial-mesenchymal interactions in pulmonary fibrosis. Annu Rev Physiol 73:413–435PubMedCrossRefGoogle Scholar
  16. Chen LJ, Ye H, Zhang Q, Li FZ, Song LJ, Yang J, Mu Q, Rao SS, Cai PC, Xiang F, Zhang JC, Su Y, Xin JB, Ma WL (2015) Bleomycin induced epithelial-mesenchymal transition (EMT) in pleural mesothelial cells. Toxicol Appl Pharmacol 283:75–82PubMedCrossRefGoogle Scholar
  17. Chmielowiec J, Borowiak M, Morkel M, Stradal T, Munz B, Werner S, Wehland J, Birchmeier C, Birchmeier W (2007) c-Met is essential for wound healing in the skin. J Cell Biol 177:151–162PubMedPubMedCentralCrossRefGoogle Scholar
  18. Ciruna BG, Schwartz L, Harpal K, Yamaguchi TP, Rossant J (1997) Chimeric analysis of fibroblast growth factor receptor-1 (Fgfr1) function: a role for FGFR1 in morphogenetic movement through the primitive streak. Development 124:2829–2841PubMedGoogle Scholar
  19. Compton LA, Potash DA, Mundell NA, Barnett JV (2006) Transforming growth factor-beta induces loss of epithelial character and smooth muscle cell differentiation in epicardial cells. Dev Dyn 235:82–93PubMedCrossRefGoogle Scholar
  20. Coulombe PA (2003) Wound epithelialization: accelerating the pace of discovery. J Invest Dermatol 121:219–230PubMedCrossRefGoogle Scholar
  21. Crosby LM, Waters CM (2010) Epithelial repair mechanisms in the lung. Am J Physiol Lung Cell Mol Physiol 298:L715–L731PubMedPubMedCentralCrossRefGoogle Scholar
  22. Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–584PubMedCrossRefGoogle Scholar
  23. Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G (1993) Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 122:103–111CrossRefPubMedGoogle Scholar
  24. Desmouliere A, Redard M, Darby I, Gabbiani G (1995) Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 146:56–66PubMedPubMedCentralGoogle Scholar
  25. Di Vita G, Patti R, D’Agostino P, Caruso G, Arcara M, Buscemi S, Bonventre S, Ferlazzo V, Arcoleo F, Cillari E (2006) Cytokines and growth factors in wound drainage fluid from patients undergoing incisional hernia repair. Wound Repair Regen 14:259–264CrossRefPubMedGoogle Scholar
  26. Diaz R, Kim JW, Hui JJ, Li Z, Swain GP, Fong KS, Csiszar K, Russo PA, Rand EB, Furth EE, Wells RG (2008) Evidence for the epithelial to mesenchymal transition in biliary atresia fibrosis. Hum Pathol 39:102–115PubMedCrossRefGoogle Scholar
  27. Direkze NC, Forbes SJ, Brittan M, Hunt T, Jeffery R, Preston SL, Poulsom R, Hodivala-Dilke K, Alison MR, Wright NA (2003) Multiple organ engraftment by bone-marrow-derived myofibroblasts and fibroblasts in bone-marrow-transplanted mice. Stem Cells 21:514–520PubMedCrossRefGoogle Scholar
  28. Dong C, Zhu S, Wang T, Yoon W, Li Z, Alvarez RJ, ten Dijke P, White B, Wigley FM, Goldschmidt-Clermont PJ (2002) Deficient Smad7 expression: a putative molecular defect in scleroderma. Proc Natl Acad Sci U S A 99:3908–3913PubMedPubMedCentralCrossRefGoogle Scholar
  29. Ebihara Y, Masuya M, Larue AC, Fleming PA, Visconti RP, Minamiguchi H, Drake CJ, Ogawa M (2006) Hematopoietic origins of fibroblasts. II. In vitro studies of fibroblasts, CFU-F, and fibrocytes. Exp Hematol 34:219–229PubMedCrossRefGoogle Scholar
  30. Eming SA, Martin P, Tomic-Canic M (2014) Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med 6:265sr266CrossRefGoogle Scholar
  31. Fan JM, Ng YY, Hill PA, Nikolic-Paterson DJ, Mu W, Atkins RC, Lan HY (1999) Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro. Kidney Int 56:1455–1467PubMedCrossRefGoogle Scholar
  32. Frid MG, Kale VA, Stenmark KR (2002) Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis. Circ Res 90:1189–1196PubMedCrossRefGoogle Scholar
  33. Friedman SL, Roll FJ, Boyles J, Bissell DM (1985) Hepatic lipocytes: the principal collagen-producing cells of normal rat liver. Proc Natl Acad Sci U S A 82:8681–8685PubMedPubMedCentralCrossRefGoogle Scholar
  34. Gabbiani G (2003) The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 200:500–503PubMedCrossRefGoogle Scholar
  35. Gabbiani G, Ryan GB, Majne G (1971) Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia 27:549–550PubMedCrossRefGoogle Scholar
  36. Gawronska-Kozak B, Grabowska A, Kur-Piotrowska A, Kopcewicz M (2016) Foxn1 transcription factor regulates wound healing of skin through promoting epithelial-mesenchymal transition. PLoS One 11:e0150635PubMedCrossRefPubMedCentralGoogle Scholar
  37. Gazi H, Pope JE, Clements P, Medsger TA, Martin RW, Merkel PA, Kahaleh B, Wollheim FA, Baron M, Csuka ME, Emery P, Belch JF, Hayat S, Lally EV, Korn JH, Czirjak L, Herrick A, Voskuyl AE, Bruehlmann P, Inanc M, Furst DE, Black C, Ellman MH, Moreland LW, Rothfield NF, Hsu V, Mayes M, McKown KM, Krieg T, Siebold JR (2007) Outcome measurements in scleroderma: results from a delphi exercise. J Rheumatol 34:501–509PubMedGoogle Scholar
  38. Gilles C, Polette M, Zahm JM, Tournier JM, Volders L, Foidart JM, Birembaut P (1999) Vimentin contributes to human mammary epithelial cell migration. J Cell Sci 112:4615–4625PubMedGoogle Scholar
  39. Golinko MS, Joffe R, de Vinck D, Chandrasekaran E, Stojadinovic O, Barrientos S, Vukelic S, Tomic-Canic M, Brem H (2009) Surgical pathology to describe the clinical margin of debridement of chronic wounds using a wound electronic medical record. J Am Coll Surg 209:254–260PubMedCrossRefGoogle Scholar
  40. Gressner AM, Weiskirchen R (2006) Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 10:76–99PubMedCrossRefGoogle Scholar
  41. Grotegut S, von Schweinitz D, Christofori G, Lehembre F (2006) Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail. EMBO J 25:3534–3545PubMedPubMedCentralCrossRefGoogle Scholar
  42. Higashiyama R, Nakao S, Shibusawa Y, Ishikawa O, Moro T, Mikami K, Fukumitsu H, Ueda Y, Minakawa K, Tabata Y, Bou-Gharios G, Inagaki Y (2011) Differential contribution of dermal resident and bone marrow-derived cells to collagen production during wound healing and fibrogenesis in mice. J Invest Dermatol 131:529–536PubMedCrossRefGoogle Scholar
  43. Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, Saito Y, Johnson RS, Kretzler M, Cohen CD, Eckardt KU, Iwano M, Haase VH (2007) Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 117:3810–3820PubMedPubMedCentralGoogle Scholar
  44. Hinz B, Gabbiani G (2003) Cell-matrix and cell-cell contacts of myofibroblasts: role in connective tissue remodeling. Thromb Haemost 90:993–1002PubMedGoogle Scholar
  45. Hong KM, Belperio JA, Keane MP, Burdick MD, Strieter RM (2007) Differentiation of human circulating fibrocytes as mediated by transforming growth factor-beta and peroxisome proliferator-activated receptor gamma. J Biol Chem 282:22910–22920PubMedCrossRefGoogle Scholar
  46. Huang RY, Guilford P, Thiery JP (2012) Early events in cell adhesion and polarity during epithelial-mesenchymal transition. J Cell Sci 125:4417–4422PubMedCrossRefGoogle Scholar
  47. Hudson LG, Newkirk KM, Chandler HL, Choi C, Fossey SL, Parent AE, Kusewitt DF (2009) Cutaneous wound reepithelialization is compromised in mice lacking functional Slug (Snai2). J Dermatol Sci 56:19–26PubMedCrossRefPubMedCentralGoogle Scholar
  48. Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, Valerius MT, McMahon AP, Duffield JS (2010) Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 176:85–97PubMedPubMedCentralCrossRefGoogle Scholar
  49. Inoue T, Okada H, Takenaka T, Watanabe Y, Suzuki H (2009) A case report suggesting the occurrence of epithelial-mesenchymal transition in obstructive nephropathy. Clin Exp Nephrol 13:385–388PubMedCrossRefGoogle Scholar
  50. Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG (2002) Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 110:341–350PubMedPubMedCentralCrossRefGoogle Scholar
  51. Javelaud D, Mauviel A (2005) Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-beta: implications for carcinogenesis. Oncogene 24:5742–5750PubMedCrossRefGoogle Scholar
  52. Jechlinger M, Sommer A, Moriggl R, Seither P, Kraut N, Capodiecci P, Donovan M, Cordon-Cardo C, Beug H, Grunert S (2006) Autocrine PDGFR signaling promotes mammary cancer metastasis. J Clin Invest 116:1561–1570PubMedCentralCrossRefPubMedGoogle Scholar
  53. Jimenez SA, Feldman G, Bashey RI, Bienkowski R, Rosenbloom J (1986) Co-ordinate increase in the expression of type I and type III collagen genes in progressive systemic sclerosis fibroblasts. Biochem J 237:837–843PubMedPubMedCentralCrossRefGoogle Scholar
  54. Jordan NV, Johnson GL, Abell AN (2011) Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer. Cell Cycle 10:2865–2873PubMedPubMedCentralCrossRefGoogle Scholar
  55. Kaimori A, Potter J, Kaimori JY, Wang C, Mezey E, Koteish A (2007) Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro. J Biol Chem 282:22089–22101PubMedCrossRefGoogle Scholar
  56. Kalluri R, Neilson EG (2003) Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 112:1776–1784PubMedPubMedCentralCrossRefGoogle Scholar
  57. Kim HJ, Litzenburger BC, Cui X, Delgado DA, Grabiner BC, Lin X, Lewis MT, Gottardis MM, Wong TW, Attar RM, Carboni JM, Lee AV (2007) Constitutively active type I insulin-like growth factor receptor causes transformation and xenograft growth of immortalized mammary epithelial cells and is accompanied by an epithelial-to-mesenchymal transition mediated by NF-kappaB and snail. Mol Cell Biol 27:3165–3175PubMedPubMedCentralCrossRefGoogle Scholar
  58. Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, Chapman HA (2006) Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A 103:13180–13185PubMedPubMedCentralCrossRefGoogle Scholar
  59. King D, Yeomanson D, Bryant HE (2015) PI3King the lock: targeting the PI3K/Akt/mTOR pathway as a novel therapeutic strategy in neuroblastoma. J Pediatr Hematol Oncol 37:245–251PubMedCrossRefGoogle Scholar
  60. Krainock M, Toubat O, Danopoulos S, Beckham A, Warburton D, Kim R (2016) Epicardial epithelial-to-mesenchymal transition in heart development and disease. J Clin Med 5:27PubMedCentralCrossRefGoogle Scholar
  61. Kusewitt DF, Choi C, Newkirk KM, Leroy P, Li Y, Chavez MG, Hudson LG (2009) Slug/Snai2 is a downstream mediator of epidermal growth factor receptor-stimulated reepithelialization. J Invest Dermatol 129:491–495PubMedCrossRefGoogle Scholar
  62. Lamouille S, Derynck R (2007) Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J Cell Biol 178:437–451PubMedCentralCrossRefPubMedGoogle Scholar
  63. Lamouille S, Connolly E, Smyth JW, Akhurst RJ, Derynck R (2012) TGF-beta-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J Cell Sci 125:1259–1273PubMedPubMedCentralCrossRefGoogle Scholar
  64. Leask A, Abraham DJ, Finlay DR, Holmes A, Pennington D, Shi-Wen X, Chen Y, Venstrom K, Dou X, Ponticos M, Black C, Bernabeu C, Jackman JK, Findell PR, Connolly MK (2002) Dysregulation of transforming growth factor beta signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts. Arthritis Rheum 46:1857–1865PubMedCrossRefGoogle Scholar
  65. Lee JM, Dedhar S, Kalluri R, Thompson EW (2006) The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 172:973–981PubMedPubMedCentralCrossRefGoogle Scholar
  66. Lee KS, Buck M, Houglum K, Chojkier M (1995) Activation of hepatic stellate cells by TGF alpha and collagen type I is mediated by oxidative stress through c-myb expression. J Clin Invest 96:2461–2468PubMedPubMedCentralCrossRefGoogle Scholar
  67. Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141:1117–1134PubMedCentralCrossRefPubMedGoogle Scholar
  68. Lepilina A, Coon AN, Kikuchi K, Holdway JE, Roberts RW, Burns CG, Poss KD (2006) A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 127:607–619PubMedCrossRefGoogle Scholar
  69. Limana F, Zacheo A, Mocini D, Mangoni A, Borsellino G, Diamantini A, De Mori R, Battistini L, Vigna E, Santini M, Loiaconi V, Pompilio G, Germani A, Capogrossi MC (2007) Identification of myocardial and vascular precursor cells in human and mouse epicardium. Circ Res 101:1255–1265PubMedCrossRefGoogle Scholar
  70. Liu Y (2011) Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol 7:684–696PubMedPubMedCentralCrossRefGoogle Scholar
  71. Lo HW, Hsu SC, Xia W, Cao X, Shih JY, Wei Y, Abbruzzese JL, Hortobagyi GN, Hung MC (2007) Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res 67:9066–9076PubMedPubMedCentralCrossRefGoogle Scholar
  72. Lu Z, Ghosh S, Wang Z, Hunter T (2003) Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell 4:499–515CrossRefPubMedGoogle Scholar
  73. Lyons JG, Birkedal-Hansen B, Pierson MC, Whitelock JM, Birkedal-Hansen H (1993) Interleukin-1 beta and transforming growth factor-alpha/epidermal growth factor induce expression of M(r) 95,000 type IV collagenase/gelatinase and interstitial fibroblast-type collagenase by rat mucosal keratinocytes. J Biol Chem 268:19143–19151PubMedGoogle Scholar
  74. Martin P (1997) Wound healing—aiming for perfect skin regeneration. Science 276:75–81PubMedCrossRefGoogle Scholar
  75. Maschler S, Wirl G, Spring H, Bredow DV, Sordat I, Beug H, Reichmann E (2005) Tumor cell invasiveness correlates with changes in integrin expression and localization. Oncogene 24:2032–2041PubMedCrossRefGoogle Scholar
  76. Mathay C, Giltaire S, Minner F, Bera E, Herin M, Poumay Y (2008) Heparin-binding EGF-like growth factor is induced by disruption of lipid rafts and oxidative stress in keratinocytes and participates in the epidermal response to cutaneous wounds. J Invest Dermatol 128:717–727PubMedCrossRefGoogle Scholar
  77. McCarthy DW, Downing MT, Brigstock DR, Luquette MH, Brown KD, Abad MS, Besner GE (1996) Production of heparin-binding epidermal growth factor-like growth factor (HB-EGF) at sites of thermal injury in pediatric patients. J Invest Dermatol 106:49–56PubMedCrossRefGoogle Scholar
  78. McDonald TM, Pascual AS, Uppalapati CK, Cooper KE, Leyva KJ, Hull EE (2013) Zebrafish keratocyte explant cultures as a wound healing model system: differential gene expression and morphological changes support epithelial-mesenchymal transition. Exp Cell Res 319:1815–1827PubMedCrossRefGoogle Scholar
  79. Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, Pradere JP, Schwabe RF (2013) Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 4:2823PubMedPubMedCentralCrossRefGoogle Scholar
  80. Mendez MG, Kojima S, Goldman RD (2010) Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J 24:1838–1851PubMedPubMedCentralCrossRefGoogle Scholar
  81. Mikawa T, Fischman DA (1992) Retroviral analysis of cardiac morphogenesis: discontinuous formation of coronary vessels. Proc Natl Acad Sci U S A 89:9504–9508PubMedPubMedCentralCrossRefGoogle Scholar
  82. Mikawa T, Gourdie RG (1996) Pericardial mesoderm generates a population of coronary smooth muscle cells migrating into the heart along with ingrowth of the epicardial organ. Dev Biol 174:221–232PubMedCrossRefGoogle Scholar
  83. Moore AW, McInnes L, Kreidberg J, Hastie ND, Schedl A (1999) YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis. Development 126:1845–1857PubMedGoogle Scholar
  84. Moreno-Bueno G, Portillo F, Cano A (2008) Transcriptional regulation of cell polarity in EMT and cancer. Oncogene 27:6958–6969PubMedCrossRefGoogle Scholar
  85. Mubarak KK, Montes-Worboys A, Regev D, Nasreen N, Mohammed KA, Faruqi I, Hensel E, Baz MA, Akindipe OA, Fernandez-Bussy S, Nathan SD, Antony VB (2012) Parenchymal trafficking of pleural mesothelial cells in idiopathic pulmonary fibrosis. Eur Respir J 39:133–140PubMedCrossRefGoogle Scholar
  86. Murillo MM, del Castillo G, Sanchez A, Fernandez M, Fabregat I (2005) Involvement of EGF receptor and c-Src in the survival signals induced by TGF-beta1 in hepatocytes. Oncogene 24:4580–4587CrossRefPubMedGoogle Scholar
  87. Nawshad A, Hay ED (2003) TGFbeta3 signaling activates transcription of the LEF1 gene to induce epithelial mesenchymal transformation during mouse palate development. J Cell Biol 163:1291–1301PubMedPubMedCentralCrossRefGoogle Scholar
  88. Nikitorowicz-Buniak J, Denton CP, Abraham D, Stratton R (2015) Partially evoked epithelial-mesenchymal transition (EMT) is associated with increased TGFbeta signaling within lesional scleroderma skin. PLoS One 10:e0134092PubMedCentralCrossRefPubMedGoogle Scholar
  89. Nishitani Y, Iwano M, Yamaguchi Y, Harada K, Nakatani K, Akai Y, Nishino T, Shiiki H, Kanauchi M, Saito Y, Neilson EG (2005) Fibroblast-specific protein 1 is a specific prognostic marker for renal survival in patients with IgAN. Kidney Int 68:1078–1085PubMedCrossRefGoogle Scholar
  90. O’Connor JW, Gomez EW (2013) Cell adhesion and shape regulate TGF-beta1-induced epithelial-myofibroblast transition via MRTF-A signaling. PLoS One 8:e83188PubMedPubMedCentralCrossRefGoogle Scholar
  91. Okada H, Danoff TM, Kalluri R, Neilson EG (1997) Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol 273:F563–F574PubMedGoogle Scholar
  92. Okada H, Ban S, Nagao S, Takahashi H, Suzuki H, Neilson EG (2000) Progressive renal fibrosis in murine polycystic kidney disease: an immunohistochemical observation. Kidney Int 58:587–597PubMedCrossRefGoogle Scholar
  93. Omenetti A, Porrello A, Jung Y, Yang L, Popov Y, Choi SS, Witek RP, Alpini G, Venter J, Vandongen HM, Syn WK, Baroni GS, Benedetti A, Schuppan D, Diehl AM (2008) Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest 118:3331–3342PubMedPubMedCentralGoogle Scholar
  94. Poelmann RE, Gittenberger-de Groot AC, Mentink MM, Bokenkamp R, Hogers B (1993) Development of the cardiac coronary vascular endothelium, studied with antiendothelial antibodies, in chicken-quail chimeras. Circ Res 73:559–568PubMedCrossRefGoogle Scholar
  95. Postlethwaite AE, Shigemitsu H, Kanangat S (2004) Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis. Curr Opin Rheumatol 16:733–738PubMedCrossRefGoogle Scholar
  96. Powers CJ, McLeskey SW, Wellstein A (2000) Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 7:165–197PubMedCrossRefGoogle Scholar
  97. Qin Y, Capaldo C, Gumbiner BM, Macara IG (2005) The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin. J Cell Biol 171:1061–1071PubMedPubMedCentralCrossRefGoogle Scholar
  98. Radisky DC, Kenny PA, Bissell MJ (2007) Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem 101:830–839PubMedPubMedCentralCrossRefGoogle Scholar
  99. Ramirez H, Patel SB, Pastar I (2014) The role of TGFbeta signaling in wound epithelialization. Adv Wound Care 3:482–491CrossRefGoogle Scholar
  100. Rangel MC, Karasawa H, Castro NP, Nagaoka T, Salomon DS, Bianco C (2012) Role of Cripto-1 during epithelial-to-mesenchymal transition in development and cancer. Am J Pathol 180:2188–2200PubMedPubMedCentralCrossRefGoogle Scholar
  101. Rastaldi MP, Ferrario F, Giardino L, Dell’Antonio G, Grillo C, Grillo P, Strutz F, Muller GA, Colasanti G, D’Amico G (2002) Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney Int 62:137–146PubMedCrossRefGoogle Scholar
  102. Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, Fauci AS (1986) Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A 83:4167–4171PubMedPubMedCentralCrossRefGoogle Scholar
  103. Ronnov-Jessen L, Petersen OW (1993) Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab Invest 68:696–707PubMedGoogle Scholar
  104. Rygiel KA, Robertson H, Marshall HL, Pekalski M, Zhao L, Booth TA, Jones DE, Burt AD, Kirby JA (2008) Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease. Lab Invest 88:112–123PubMedCrossRefGoogle Scholar
  105. Santoro MM, Gaudino G (2005) Cellular and molecular facets of keratinocyte reepithelization during wound healing. Exp Cell Res 304:274–286PubMedCrossRefGoogle Scholar
  106. Sasaki T (1992) The effects of basic fibroblast growth factor and doxorubicin on cultured human skin fibroblasts: relevance to wound healing. J Dermatol 19:664–666PubMedCrossRefGoogle Scholar
  107. Savagner P (2001) Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays 23:912–923CrossRefPubMedGoogle Scholar
  108. Savagner P, Yamada KM, Thiery JP (1997) The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition. J Cell Biol 137:1403–1419PubMedPubMedCentralCrossRefGoogle Scholar
  109. Savagner P, Kusewitt DF, Carver EA, Magnino F, Choi C, Gridley T, Hudson LG (2005) Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes. J Cell Physiol 202:858–866PubMedCrossRefGoogle Scholar
  110. Serini G, Gabbiani G (1999) Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res 250:273–283PubMedCrossRefGoogle Scholar
  111. Shirley SH, Hudson LG, He J, Kusewitt DF (2010) The skinny on Slug. Mol Carcinog 49:851–861PubMedPubMedCentralCrossRefGoogle Scholar
  112. Shiwen X, Stratton R, Nikitorowicz-Buniak J, Ahmed-Abdi B, Ponticos M, Denton C, Abraham D, Takahashi A, Suki B, Layne MD, Lafyatis R, Smith BD (2015) A role of myocardin related transcription factor-A (MRTF-A) in scleroderma related fibrosis. PLoS One 10:e0126015PubMedPubMedCentralCrossRefGoogle Scholar
  113. Smart N, Dube KN, Riley PR (2013) Epicardial progenitor cells in cardiac regeneration and neovascularisation. Vasc Pharmacol 58:164–173CrossRefGoogle Scholar
  114. Smith BN, Bhowmick NA (2016) Role of EMT in metastasis and therapy resistance. J Clin Med 5:17CrossRefPubMedCentralGoogle Scholar
  115. Sogabe Y, Abe M, Yokoyama Y, Ishikawa O (2006) Basic fibroblast growth factor stimulates human keratinocyte motility by Rac activation. Wound Repair Regen 14:457–462PubMedCrossRefGoogle Scholar
  116. Sonnylal S, Denton CP, Zheng B, Keene DR, He R, Adams HP, Vanpelt CS, Geng YJ, Deng JM, Behringer RR, de Crombrugghe B (2007) Postnatal induction of transforming growth factor beta signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma. Arthritis Rheum 56:334–344PubMedCrossRefGoogle Scholar
  117. Stoll S, Garner W, Elder J (1997) Heparin-binding ligands mediate autocrine epidermal growth factor receptor activation in skin organ culture. J Clin Invest 100:1271–1281PubMedPubMedCentralCrossRefGoogle Scholar
  118. Stoll SW, Rittie L, Johnson JL, Elder JT (2012) Heparin-binding EGF-like growth factor promotes epithelial-mesenchymal transition in human keratinocytes. J Invest Dermatol 132:2148–2157PubMedCentralCrossRefPubMedGoogle Scholar
  119. Strizzi L, Bianco C, Normanno N, Seno M, Wechselberger C, Wallace-Jones B, Khan NI, Hirota M, Sun Y, Sanicola M, Salomon DS (2004) Epithelial mesenchymal transition is a characteristic of hyperplasias and tumors in mammary gland from MMTV-Cripto-1 transgenic mice. J Cell Physiol 201:266–276PubMedCrossRefGoogle Scholar
  120. Strutz F, Zeisberg M, Ziyadeh FN, Yang CQ, Kalluri R, Muller GA, Neilson EG (2002) Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int 61:1714–1728PubMedCrossRefGoogle Scholar
  121. Sun X, Meyers EN, Lewandoski M, Martin GR (1999) Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev 13:1834–1846PubMedPubMedCentralCrossRefGoogle Scholar
  122. Takenawa T, Suetsugu S (2007) The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol 8:37–48PubMedCrossRefGoogle Scholar
  123. Tan B, Pascual A, de Beus A, Cooper K, Hull E (2011) TGFbeta (transforming growth factor beta) and keratocyte motility in 24 h zebrafish explant cultures. Cell Biol Int 35:1131–1139PubMedCrossRefGoogle Scholar
  124. Tao Q, Yokota C, Puck H, Kofron M, Birsoy B, Yan D, Asashima M, Wylie CC, Lin X, Heasman J (2005) Maternal wnt11 activates the canonical wnt signaling pathway required for axis formation in Xenopus embryos. Cell 120:857–871PubMedCrossRefGoogle Scholar
  125. Terao M, Ishikawa A, Nakahara S, Kimura A, Kato A, Moriwaki K, Kamada Y, Murota H, Taniguchi N, Katayama I, Miyoshi E (2011) Enhanced epithelial-mesenchymal transition-like phenotype in N-acetylglucosaminyltransferase V transgenic mouse skin promotes wound healing. J Biol Chem 286:28303–28311PubMedPubMedCentralCrossRefGoogle Scholar
  126. Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142CrossRefPubMedGoogle Scholar
  127. Toyoda M, Takayama H, Horiguchi N, Otsuka T, Fukusato T, Merlino G, Takagi H, Mori M (2001) Overexpression of hepatocyte growth factor/scatter factor promotes vascularization and granulation tissue formation in vivo. FEBS Lett 509:95–100PubMedCrossRefGoogle Scholar
  128. Tsai JH, Yang J (2013) Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev 27:2192–2206PubMedPubMedCentralCrossRefGoogle Scholar
  129. Valles AM, Boyer B, Tarone G, Thiery JP (1996) Alpha 2 beta 1 integrin is required for the collagen and FGF-1 induced cell dispersion in a rat bladder carcinoma cell line. Cell Adhes Commun 4:187–199CrossRefPubMedGoogle Scholar
  130. Vincent T, Neve EP, Johnson JR, Kukalev A, Rojo F, Albanell J, Pietras K, Virtanen I, Philipson L, Leopold PL, Crystal RG, de Herreros AG, Moustakas A, Pettersson RF, Fuxe J (2009) A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition. Nat Cell Biol 11:943–950PubMedCrossRefPubMedCentralGoogle Scholar
  131. Volk SW, Iqbal SA, Bayat A (2013) Interactions of the extracellular matrix and progenitor cells in cutaneous wound healing. Adv Wound Care 2:261–272CrossRefGoogle Scholar
  132. Wang Y, Weil BR, Herrmann JL, Abarbanell AM, Tan J, Markel TA, Kelly ML, Meldrum DR (2009) MEK, p38, and PI-3K mediate cross talk between EGFR and TNFR in enhancing hepatocyte growth factor production from human mesenchymal stem cells. Am J Physiol Cell Physiol 297:C1284–C1293PubMedPubMedCentralCrossRefGoogle Scholar
  133. Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y, Johnson KR (2008) Cadherin switching. J Cell Sci 121:727–735CrossRefPubMedGoogle Scholar
  134. Whiteman EL, Liu CJ, Fearon ER, Margolis B (2008) The transcription factor snail represses Crumbs3 expression and disrupts apico-basal polarity complexes. Oncogene 27:3875–3879PubMedPubMedCentralCrossRefGoogle Scholar
  135. Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, Borok Z (2005) Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol 166:1321–1332PubMedPubMedCentralCrossRefGoogle Scholar
  136. Winter EM, Grauss RW, Hogers B, van Tuyn J, van der Geest R, Lie-Venema H, Steijn RV, Maas S, Deruiter MC, DeVries AA, Steendijk P, Doevendans PA, van der Laarse A, Poelmann RE, Schalij MJ, Atsma DE, Gittenberger-de Groot AC (2007) Preservation of left ventricular function and attenuation of remodeling after transplantation of human epicardium-derived cells into the infarcted mouse heart. Circulation 116:917–927PubMedCrossRefGoogle Scholar
  137. Wynn TA, Ramalingam TR (2012) Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 18:1028–1040PubMedPubMedCentralCrossRefGoogle Scholar
  138. Xu J, Lamouille S, Derynck R (2009) TGF-beta-induced epithelial to mesenchymal transition. Cell Res 19:156–172PubMedCrossRefPubMedCentralGoogle Scholar
  139. Xu L, Chen YG, Massague J (2000) The nuclear import function of Smad2 is masked by SARA and unmasked by TGFbeta-dependent phosphorylation. Nat Cell Biol 2:559–562PubMedCrossRefGoogle Scholar
  140. Yan C, Grimm WA, Garner WL, Qin L, Travis T, Tan N, Han YP (2010) Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2. Am J Pathol 176:2247–2258PubMedPubMedCentralCrossRefGoogle Scholar
  141. Yang X, Pursell B, Lu S, Chang TK, Mercurio AM (2009) Regulation of beta 4-integrin expression by epigenetic modifications in the mammary gland and during the epithelial-to-mesenchymal transition. J Cell Sci 122:2473–2480PubMedPubMedCentralCrossRefGoogle Scholar
  142. Yoshida S, Yamaguchi Y, Itami S, Yoshikawa K, Tabata Y, Matsumoto K, Nakamura T (2003) Neutralization of hepatocyte growth factor leads to retarded cutaneous wound healing associated with decreased neovascularization and granulation tissue formation. J Invest Dermatol 120:335–343PubMedCrossRefGoogle Scholar
  143. You S, Avidan O, Tariq A, Ahluwalia I, Stark PC, Kublin CL, Zoukhri D (2012) Role of epithelial-mesenchymal transition in repair of the lacrimal gland after experimentally induced injury. Invest Ophthalmol Vis Sci 53:126–135PubMedPubMedCentralCrossRefGoogle Scholar
  144. Zeisberg M, Bonner G, Maeshima Y, Colorado P, Muller GA, Strutz F, Kalluri R (2001) Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiation. Am J Pathol 159:1313–1321PubMedPubMedCentralCrossRefGoogle Scholar
  145. Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R (2003) BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9:964–968PubMedCrossRefGoogle Scholar
  146. Zhang YM, Zhang ZQ, Liu YY, Zhou X, Shi XH, Jiang Q, Fan DL, Cao C (2015) Requirement of Galphai1/3-Gab1 signaling complex for keratinocyte growth factor-induced PI3K-AKT-mTORC1 activation. J Invest Dermatol 135:181–191CrossRefPubMedGoogle Scholar
  147. Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC (2004) Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 6:931–940PubMedCrossRefGoogle Scholar
  148. Zhou G, Dada LA, Wu M, Kelly A, Trejo H, Zhou Q, Varga J, Sznajder JI (2009) Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1. Am J Physiol Lung Cell Mol Physiol 297:L1120–L1130PubMedPubMedCentralCrossRefGoogle Scholar
  149. Zolak JS, Jagirdar R, Surolia R, Karki S, Oliva O, Hock T, Guroji P, Ding Q, Liu RM, Bolisetty S, Agarwal A, Thannickal VJ, Antony VB (2013) Pleural mesothelial cell differentiation and invasion in fibrogenic lung injury. Am J Pathol 182:1239–1247PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Rivka C. Stone
    • 1
    • 2
  • Irena Pastar
    • 1
  • Nkemcho Ojeh
    • 1
    • 3
  • Vivien Chen
    • 1
  • Sophia Liu
    • 1
  • Karen I. Garzon
    • 1
  • Marjana Tomic-Canic
    • 1
  1. 1.Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous SurgeryUniversity of Miami Miller School of MedicineMiamiUSA
  2. 2.The Research Residency Program, Department of Dermatology and Cutaneous SurgeryUniversity of Miami Miller School of MedicineMiamiUSA
  3. 3.Faculty of Medical SciencesThe University of the West IndiesBridgetownBarbados

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