Epithelial-mesenchymal transition and its implications for fibrosis.
Journal: 2004/January - Journal of Clinical Investigation
ISSN: 0021-9738
Epithelial to mesenchymal transition (EMT) is a central mechanism for diversifying the cells found in complex tissues. This dynamic process helps organize the formation of the body plan, and while EMT is well studied in the context of embryonic development, it also plays a role in the genesis of fibroblasts during organ fibrosis in adult tissues. Emerging evidence from studies of renal fibrosis suggests that more than a third of all disease-related fibroblasts originate from tubular epithelia at the site of injury. This review highlights recent advances in the process of EMT signaling in health and disease and how it may be attenuated or reversed by selective cytokines and growth factors.
Similar articles
Articles by the same authors
Discussion board
J Clin Invest 112(12): 1776-1784

Epithelial-mesenchymal transition and its implications for fibrosis

Center for Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA Departments of Medicine and Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Address correspondence to: Raghu Kalluri, Center for Matrix Biology, Beth Israel Deaconess Medical Center, 330 Brookline Ave. (DANA 514), Boston, Massachusetts 02215, USA. Phone: (617) 667-0455; Fax: (617) 975-5663; E-mail: ude.dravraH.CMDIB@irullaKr.
Address correspondence to: Raghu Kalluri, Center for Matrix Biology, Beth Israel Deaconess Medical Center, 330 Brookline Ave. (DANA 514), Boston, Massachusetts 02215, USA. Phone: (617) 667-0455; Fax: (617) 975-5663; E-mail: ude.dravraH.CMDIB@irullaKr.


Epithelial to mesenchymal transition (EMT) is a central mechanism for diversifying the cells found in complex tissues. This dynamic process helps organize the formation of the body plan, and while EMT is well studied in the context of embryonic development, it also plays a role in the genesis of fibroblasts during organ fibrosis in adult tissues. Emerging evidence from studies of renal fibrosis suggests that more than a third of all disease-related fibroblasts originate from tubular epithelia at the site of injury. This review highlights recent advances in the process of EMT signaling in health and disease and how it may be attenuated or reversed by selective cytokines and growth factors.


For one hundred and forty-five years, biologists have known that cells come from cells (1). This concept is so fundamental today that we accept it implicitly; cells either divide asymmetrically to preserve stem cell progenitors, partition into sister cells, differentiate along fate pathways, or undergo oncogenesis following the formation of normal tissues. Specification and diversification of cell lineages are initiated by genetic programs under the control of morphogenic cues (24). These lineages evolve in a hierarchical manner conforming to developmental boundaries and oscillating biological clocks until reaching terminal differentiation (5). Epithelia from metazoans are emblematic of this process, and at maturity cover outer surfaces (6, 7) or line hollow cavities formed by tubular structures in complex tissues (810). Since epithelia typically serve specialized functions (1113), it is assumed that a state of terminal differentiation is necessary and protected once development is complete.

In recent years, however, this formidable notion has been challenged by observations that mature epithelia change their phenotype following morphogenic pressure from injured tissue. Since the phenomenon of epithelial plasticity was described before it had a firm biochemical basis (14, 15), one is confronted with a plethora of seemingly interchangeable vocabulary. Today, the terms “epithelial-mesenchymal transformation, interactions, or transition” are comingled inappropriately with the term “epithelial-mesenchymal transdifferentiation.” “Transformation” classically describes the oncogenic conversion of epithelia. Likewise, the induction of bone marrow stem cells to form somatic cells probably should be considered differentiation rather than transdifferentiation (16). Epithelial-mesenchymal interaction refers to proximate paracrine cross-talk between tissue epithelia and stromal fibroblasts and is completely different from the concept of epithelial-mesenchymal transition (EMT). EMT is a variant of transdifferentiation and a well-recognized mechanism for dispersing cells in vertebrate embryos (17), forming fibroblasts in injured tissues (18, 19), or initiating metastases in epithelial cancer (2023). We prefer the term “transition” to describe this conversion instead of “epithelial-mesenchymal transdifferentiation” because “transdifferentiation” classically refers to differentiated cells changing into other differentiated cells (24). Transdifferentiation has been observed in retinal pigmented cells that become lens epithelia (25, 26), in the conversion from white to brown adipocytes (27), endothelial cells that become vascular smooth muscle cells (28), lactotrophs that interconvert to somatotrophs in the pituitary (29), pancreatic acinar cells that become ductal epithelium (30, 31) or hepatocytes (32, 33), and hepatocytes that morph into pancreatic ductal cells (34). Although many investigators fail to make the distinction between transdifferentiation and transition, it may be time to do so. It is not yet clear whether the fibroblast transition of EMT is an expected middle phase of transdifferentiating epithelium or whether EMT producing fibroblasts is an arrested form of transdifferentiation (24). EMT of terminally differentiated epithelium, in its purest sense, produces a tissue fibroblast (19).

Developmental biologists have also known for decades that epiblasts undergo EMT to form primary mesenchyme in the creation of tripoblastic germ layers (17, 3537; Figure Figure1).1). In the mesoderm this is followed by mesenchymal-epithelial transitions to create secondary epithelium as part of somitogenesis (38, 39) and the further commitment and diversification of cells forming mesoendodermal structures (4042). Secondary epithelium in mature or adult tissues can also undergo EMT following epithelial stress, such as inflammation (18, 19) or wounding (17, 43) that leads to fibroblast production and fibrogenesis. Epithelia forming tumors also use EMT when carcinomas become metastatic (23, 44, 45).

An external file that holds a picture, illustration, etc.
Object name is JCI0320530.f1.jpg

Primitive epithelia (epiblasts) form tropoblastic germ layers through EMT. The primary mesenchyme that migrates after EMT is reinduced to secondary epithelium by mesenchymal-epithelial transition. Secondary epithelia differentiate to form new epithelial tissues and undergo a second round of EMT to form the cells of connective tissue, including astrocytes, adipocytes chondrocytes, osteoblasts, muscle cells, and fibroblasts. Mature secondary epithelia that form epithelial organs can also transform into primary tumors that later undergo EMT to metastasize. These processes are regulated by morphogenic cues and a variety of transcription factors, and are potentially plastic in their adaptation to new biologic circumstances.

We review here recent observations regarding the mechanism of EMT in culture and during fibrogenesis, especially associated with kidney disease. The problem of tissue fibrosis is that epithelial units are overtaken by scarification and lose their morphogenic cues, leaving involved organs to fail. While traditional studies of fibrosis have focused on the production of extracellular matrix, recent information now suggests that epithelia contribute to the problem by creating new fibroblasts. Experiments demonstrating the reversibility of organ fibrosis also highlight the need to consider cellular mechanisms of fibrogenesis and the basic biology that will, one hopes, contribute new molecules as useful therapeutics.


This work was supported by grants NIH/DK55001, and NIH/DK62987, The Espinosa Liver Fibrosis Fund, and research support from the Center for Matrix Biology at Beth Israel Deaconess Medical Center, all to R. Kalluri. E. Neilson is supported by NIH/DK46282 and Yamanouchi USA Foundation.



Conflict of interest: The authors have declared that no conflict of interest exists.

Nonstandard abbreviations used: epithelial-mesenchymal transition (EMT); bone morphogenic protein 7 (BMP-7); integrin-linked kinase (ILK); lymphoid enhancer factor (LEF); glycogen synthase kinase (GSK); fibroblast-specific protein-1 (FSP1); α-smooth muscle actin (αSMA); tubular basement membrane (TBM); tissue plasminogen activator (tPA).



  • 1. Virchow, R1858. Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre. A. Hirschwald. Berlin, Germany. 456 pp.
  • 2. Slack JMWStem cells in epithelial tissues. Science.2000;287:1431–1433.[PubMed]
  • 3. Watt FM, Hogan BLOut of Eden: stem cells and their niches. Science.2000;287:1427–1430.[PubMed]
  • 4. Blau HM, Brazelton TR, Weimann JMThe evolving concept of a stem cell: entity or function? Cell.2001;105:829–841.[PubMed]
  • 5. Irvine KD, Rauskolb CBoundaries in development: formation and function. Annu. Rev. Cell Dev. Biol.2001;17:189–214.[PubMed]
  • 6. Sengel PPattern formation in skin development. Int. J. Dev. Biol.1990;34:33–50.[PubMed]
  • 7. Erickson CA, Reedy MVNeural crest development: the interplay between morphogenesis and cell differentiation. Curr. Top. Dev. Biol.1998;40:177–209.[PubMed]
  • 8. Hogan BL, Kolodziej PAOrganogenesis: molecular mechanisms of tubulogenesis. Nat. Rev. Genet.2002;3:513–523.[PubMed]
  • 9. Krasnow MA, Nelson WJTube morphogenesis. Trends Cell Biol.2002;12:351.[PubMed]
  • 10. Lubarsky B, Krasnow MATube morphogenesis: making and shaping biological tubes. Cell.2003;112:19–28.[PubMed]
  • 11. Gumbiner BMEpithelial morphogenesis. Cell.1992;69:385–387.[PubMed]
  • 12. Yeaman C, Grindstaff KK, Hansen MD, Nelson WJCell polarity: versatile scaffolds keep things in place. Curr. Biol.1999;9:R515–517.[PubMed]
  • 13. Al-Awqati Q, Vijayakumar S, Takito JTerminal differentiation of epithelia. Biol. Chem.2003;384:1255–1258.[PubMed]
  • 14. Boyer B, Valles AM, Edme NInduction and regulation of epithelial-mesenchymal transitions. Biochem. Pharmacol.2000;60:1091–1099.[PubMed]
  • 15. Nieto MAThe snail superfamily of zinc-finger transcription factors. Nat. Rev. Mol. Cell Biol.2002;3:155–166.[PubMed]
  • 16. Tsai RY, Kittappa R, McKay RDPlasticity, niches, and the use of stem cells. Dev. Cell.2002;2:707–712.[PubMed]
  • 17. Hay EDAn overview of epithelio-mesenchymal transformations. Acta Anat.1995;154:8–20.[PubMed]
  • 18. Strutz F, et al Identification and characterization of a fibroblast marker: FSP1. J. Cell Biol.1995;130:393–405.
  • 19. Iwano M, et al Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest.2002;110:341–350. doi:10.1172/JCI200215518.
  • 20. Kiemer AK, Takeuchi K, Quinlan MPIdentification of genes involved in epithelial-mesenchymal transition and tumor progression. Oncogene.2001;20:6679–6688.[PubMed]
  • 21. Janda E, et al Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J. Cell Biol.2002;156:299–313.
  • 22. Vincent-Salomon A, Thiery JPHost microenvironment in breast cancer development: epithelial-mesenchymal transition in breast cancer development. Breast Cancer Res.2003;5:101–106.
  • 23. Xue C, Plieth D, Venkov C, Xu C, Neilson EGThe gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastases. Cancer Res.2003;63:3386–3394.[PubMed]
  • 24. Slack JM, Tosh DTransdifferentiation and metaplasia–switching cell types. Curr. Opin. Genet.Dev.2001;11:581–586.[PubMed]
  • 25. Eguchi G, Kodama RTransdifferentiation. Curr. Opin. Cell Biol.1993;5:1023–1028.[PubMed]
  • 26. Rio-Tsonis KD, Tsonis PAEye regeneration at the molecular age. Dev. Dyn.2003;226:211–224.[PubMed]
  • 27. Cinti SAdipocyte differentiation and transdifferentiation: plasticity of the adipose organ. J. Endocrinol. Invest.2002;25:823–835.[PubMed]
  • 28. Frid MG, Kale VA, Stenmark KRMature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis. Circ. Res.2002;90:1189–1196.[PubMed]
  • 29. Vidal S, Horvath E, Kovacs K, Lloyd RV, Smyth HSReversible transdifferentiation: interconversion of somatotrophs and lactotrophs in pituitary hyperplasia. Mod. Pathol.2001;14:20–28.[PubMed]
  • 30. Rooman I, Heremans Y, Heimberg H, Bouwens LModulation of rat pancreatic acinoductal transdifferentiation and expression of PDX-1 in vitro. Diabetologia.2000;43:907–914.[PubMed]
  • 31. Hall PA, Lemoine NRRapid acinar to ductal transdifferentiation in cultured human exocrine pancreas. J. Pathol.1992;166:97–103.[PubMed]
  • 32. Shen CN, Slack JM, Tosh DMolecular basis of transdifferentiation of pancreas to liver. Nat. Cell Biol.2000;2:879–887.[PubMed]
  • 33. Shen CN, Horb ME, Slack JM, Tosh DTransdifferentiation of pancreas to liver. Mech. Dev.2003;120:107–116.[PubMed]
  • 34. Horb ME, Shen CN, Tosh D, Slack JMExperimental conversion of liver to pancreas. Curr. Biol.2003;13:105–115.[PubMed]
  • 35. Tam PP, Behringer RRMouse gastrulation: the formation of a mammalian body plan. Mech. Dev.1997;68:3–25.[PubMed]
  • 36. Narasimha M, Leptin MCell movements during gastrulation: come in and be induced. Trends Cell Biol.2000;10:169–172.[PubMed]
  • 37. Carver EA, Jiang R, Lan Y, Oram KF, Gridley TThe mouse snail gene encodes a key regulator of the epithelial-mesenchymal transition. Mol. Cell. Biol.2001;21:8184–8188.
  • 38. Summerbell D, Rigby PWTranscriptional regulation during somitogenesis. Curr. Top. Dev. Biol.2000;48:301–318.[PubMed]
  • 39. Pourquie OVertebrate somitogenesis. Annu. Rev. Cell Dev. Biol.2001;17:311–350.[PubMed]
  • 40. Ekblom PDevelopmentally regulated conversion of mesenchyme to epithelium. FASEB J.1989;3:2141–2150.[PubMed]
  • 41. Birchmeier W, Birchmeier CMesenchymal-epithelial transitions. Bioessays.1994;16:305–307.[PubMed]
  • 42. Barasch J, et al Mesenchymal to epithelial conversion in rat metanephros is induced by LIF. Cell.1999;99:377–386.[PubMed]
  • 43. Desmouliere AFactors influencing myofibroblast differentiation during wound healing and fibrosis. Cell Biol. Int.1995;19:471–476.[PubMed]
  • 44. Lochter APlasticity of mammary epithelia during normal development and neoplastic progression. Biochem.Cell Biol.1998;76:997–1008.[PubMed]
  • 45. Guarino M, Micheli P, Pallotti F, Giordano FPathological relevance of epithelial and mesenchymal phenotype plasticity. Pathol. Res. Pract.1999;195:379–389.[PubMed]
  • 46. Yang J, Liu YDissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am. J. Pathol.2001;159:1465–1475.
  • 47. Zeisberg M, Maeshima Y, Mosterman B, Kalluri R. Renal fibrosis. Extracellular matrix microenvironment regulates migratory behavior of activated tubular epithelial cells. Am. J. Pathol.2002;160:2001–2008.
  • 48. Zeisberg M, et al Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiation. Am. J. Pathol.2001;159:1313–1321.
  • 49. Fan JM, et al Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro. Kidney Int.1999;56:1455–1467.[PubMed]
  • 50. Okada H, Danoff TM, Kalluri R, Neilson EGThe early role of FSP1 in epithelial-mesenchymal transformation. Am. J. Physiol.1997;273:563–574.[PubMed]
  • 51. Morali OG, et al IGF-II induces rapid beta-catenin relocation to the nucleus during epithelium to mesenchyme transition. Oncogene.2001;20:4942–4950.[PubMed]
  • 52. Strutz F, et al Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int.2002;61:1714–1728.[PubMed]
  • 53. Bhowmick NA, Zent R, Ghiassi M, McDonnell M, Moses HLIntegrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity. J. Biol. Chem.2001;276:46707–46713.[PubMed]
  • 54. Zeisberg M, et al BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med.2003;9:964–968.[PubMed]
  • 55. Boyer AS, Erickson CP, Runyan RBEpithelial-mesenchymal transformation in the embryonic heart is mediated through distinct pertussis toxin-sensitive and TGFβ signal transduction mechanisms. Dev. Dyn.1999;214:81–91.[PubMed]
  • 56. Yu L, Hebert MC, Zhang YETGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. EMBO J.2002;21:3749–3759.
  • 57. Boyer AS, et al TGFbeta2 and TGFbeta3 have separate and sequential activities during epithelial-mesenchymal cell transformation in the embryonic heart. Dev. Biol.1999;208:530–545.[PubMed]
  • 58. Bhowmick NA, et al Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol. Biol. Cell.2001;12:27–36.
  • 59. Camenisch TD, et al Temporal and distinct TGFbeta ligand requirements during mouse and avian endocardial cushion morphogenesis. Dev. Biol.2002;248:170–181.[PubMed]
  • 60. Miettinen PJ, Ebner R, Lopez AR, Derynck RTGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J. Cell Biol.1994;127:2021–2036.
  • 61. Derynck R, Zhang YESmad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature.2003;425:577–584.[PubMed]
  • 62. Citterio HL, Gaillard DAExpression of transforming growth factor alpha (TGF alpha), epidermal growth factor receptor (EGF-R) and cell proliferation during human palatogenesis: an immunohistochemical study. Int. J. Dev. Biol.1994;38:499–505.[PubMed]
  • 63. Morabito CJ, Dettman RW, Kattan J, Collier JM, Bristow JPositive and negative regulation of epicardial-mesenchymal transformation during avian heart development. Dev. Biol.2001;234:204–215.[PubMed]
  • 64. Thery C, Stern CDRoles of kringle domain-containing serine proteases in epithelial-mesenchymal transitions during embryonic development. Acta Anat. (Basel).1996;156:162–172.[PubMed]
  • 65. Lamorte L, Royal I, Naujokas M, Park MCrk adapter proteins promote an epithelial-mesenchymal-like transition and are required for HGF-mediated cell spreading and breakdown of epithelial adherens junctions. Mol. Biol. Cell.2002;13:1449–1461.
  • 66. Song W, Majka SM, McGuire PGHepatocyte growth factor expression in the developing myocardium: evidence for a role in the regulation of the mesenchymal cell phenotype and urokinase expression. Dev. Dyn.1999;214:92–100.[PubMed]
  • 67. Thery C, Sharpe MJ, Batley SJ, Stern CD, Gherardi EExpression of HGF/SF, HGF1/MSP, and c-met suggests new functions during early chick development. Dev. Genet.1995;17:90–101.[PubMed]
  • 68. Nusrat A, et al. Hepatocyte growth factor/scatter factor effects on epithelia. Regulation of intercellular junctions in transformed and nontransformed cell lines, basolateral polarization of c-met receptor in transformed and natural intestinal epithelia, and induction of rapid wound repair in a transformed model epithelium. J. Clin. Invest.1994;93:2056–2065.
  • 69. Mizuno S, et al Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronic renal disease. J. Clin. Invest.1998;101:1827–1834.
  • 70. Etienne-Manneville S, Hall ARho GTPases in cell biology. Nature.2002;420:629–635.[PubMed]
  • 71. Bar-Sagi D, Hall ARas and Rho GTPases: a family reunion. Cell.2000;103:227–238.[PubMed]
  • 72. Savagner PLeaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays.2001;23:912–923.[PubMed]
  • 73. Kim K, Lu Z, Hay EDDirect evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol. Int.2002;26:463–476.[PubMed]
  • 74. Hall ARho GTPases and the actin cytoskeleton. Science.1998;279:509–514.[PubMed]
  • 75. Li Y, Yang J, Dai C, Wu C, Liu YRole for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis. J. Clin. Invest.2003;112:503–516. doi:10.1172/JCI200317913.
  • 76. Novak A, et al Cell adhesion and the integrin-linked kinase regulate the LEF-1 and beta-catenin signaling pathways. Proc. Natl. Acad. Sci.U. S. A.1998;95:4374–4379.
  • 77. Espada J, Perez-Moreno M, Braga VM, Rodriguez-Viciana P, Cano AH-Ras activation promotes cytoplasmic accumulation and phosphoinositide 3-OH kinase association of beta-catenin in epidermal keratinocytes. J. Cell Biol.1999;146:967–980.
  • 78. Behrens J, et al Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/beta-catenin complex in cells transformed with a temperature-sensitive v-SRC gene. J. Cell Biol.1993;120:757–766.
  • 79. Smith DE, Franco del Amo F, Gridley TIsolation of Sna, a mouse gene homologous to the Drosophila genes snail and escargot: its expression pattern suggests multiple roles during postimplantation development. Development.1992;116:1033–1039.[PubMed]
  • 80. Attisano L, Wrana JLSignal transduction by the TGF-beta superfamily. Science.2002;296:1646–1647.[PubMed]
  • 81. He XA wnt-wnt situation. Dev. Cell.2003;4:791–797.[PubMed]
  • 82. Sadot E, Geiger B, Oren M, Ben-Ze’ev ADown-regulation of beta-catenin by activated p53. Mol. Cell. Biol.2001;21:6768–6781.
  • 83. Aberle H, Bauer A, Stappert J, Kispert A, Kemler Rbeta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J.1997;16:3797–3804.
  • 84. von Kries JP, et al Hot spots in beta-catenin for interactions with LEF-1, conductin and APC. Nat. Struct. Biol.2000;7:800–807.[PubMed]
  • 85. Kim K, Hay EDNew evidence that nuclear import of endogenous beta-catenin is LEF-1 dependent, while LEF-1 independent import of exogenous beta-catenin leads to nuclear abnormalities. Cell Biol. Int.2001;25:1149–1161.[PubMed]
  • 86. Midgley CA, et al APC expression in normal human tissues. J. Pathol.1997;181:426–433.[PubMed]
  • 87. Ip YT, Gridley TCell movements during gastrulation: snail dependent and independent pathways. Curr. Opin. Genet. Dev.2002;12:423–429.[PubMed]
  • 88. Zavadil J, et al Genetic programs of epithelial cell plasticity directed by transforming growth factor-beta. Proc. Natl. Acad. Sci. U. S. A.2001;98:6686–6691.
  • 89. Ramaswamy S, Ross KN, Lander ES, Golub TRA molecular signature of metastasis in primary solid tumors. Nat. Genet.2003;33:49–54.[PubMed]
  • 90. Blau HM, Blakely BTPlasticity of cell fate: insights from heterokaryons. Semin.Cell Dev. Biol.1999;10:267–272.[PubMed]
  • 91. Emerson BMSpecificity of gene regulation. Cell.2002;109:267–270.[PubMed]
  • 92. Cremer T, Cremer CChromosome territories, nuclear architecture and gene regulation in mammalian cells. Nat. Rev. Genet.2001;2:292–301.[PubMed]
  • 93. Mannervik M, Nibu Y, Zhang H, Levine MTranscriptional coregulators in development. Science.1999;284:606–609.[PubMed]
  • 94. Young BA, Gruber TM, Gross CAViews of transcription initiation. Cell.2002;109:417–420.[PubMed]
  • 95. Peinado H, Quintanilla M, Cano A. Transforming growth factor beta 1 induces snail transcription factor in epithelial cell lines. Mechanisms for epithelial-mesenchymal transitions. J. Biol. Chem.2003;278:21113–21123.[PubMed]
  • 96. Lie-Venema H, et al Ets-1 and Ets-2 transcription factors are essential for normal coronary and myocardial development in chicken embryos. Circ. Res.2003;92:749–756.[PubMed]
  • 97. Macias D, Perez-Pomares JM, Garcia-Garrido L, Carmona R, Munoz-Chapuli RImmunoreactivity of the ets-1 transcription factor correlates with areas of epithelial-mesenchymal transition in the developing avian heart. Anat. Embryol. (Berl.).1998;198:307–315.[PubMed]
  • 98. Ridinger K, et al Clustered organization of S100 genes in human and mouse. . Biochim. Biophys. Acta.1998; 1448:254–263.[PubMed]
  • 99. Iwano M, et al Conditional abatement of tissue fibrosis using nucleoside analogs to selectively corrupt DNA replication in transgenic fibroblasts. Mol. Ther.2001;3:149–159.[PubMed]
  • 100. Barraclough RCalcium-binding protein S100A4 in health and disease. . Biochim. Biophys. Acta.1998; 1448:190–199.[PubMed]
  • 101. Grigorian M, et al Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction. J. Biol. Chem.2001;276:22699–22708.[PubMed]
  • 102. Chen H, et al Binding to intracellular targets of the metastasis-inducing protein, S100A4 (p9Ka) Biochem. Biophys. Res. Commun.2001;286:1212–1217.[PubMed]
  • 103. Ambartsumian N, et al The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor. Oncogene.2001;20:4685–4695.[PubMed]
  • 104. Okada H, et al Novel cis-acting elements in the FSP1 gene regulate fibroblast-specific transcription. Am. J. Physiol.1998;275:306–314.[PubMed]
  • 105. Tian YC, Fraser D, Attisano L, Phillips AOTGF-{beta}1-mediated alterations of renal proximal tubular epithelial cell phenotype. Am. J. Physiol. Renal Physiol.2003;285:F130–F142.[PubMed]
  • 106. Thiery JP, Chopin DEpithelial cell plasticity in development and tumor progression. Cancer Metastasis Rev.1999;18:31–42.[PubMed]
  • 107. Quilliam LA, Rebhun JF, Castro AFA growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases. Prog. Nucleic Acid Res. Mol. Biol.2002;71:391–444.[PubMed]
  • 108. Bernards AGAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. . Biochim. Biophys. Acta.2003; 1603:47–82.[PubMed]
  • 109. Masszi A, et al Central role for Rho in TGF-beta1-induced alpha-smooth muscle actin expression during epithelial-mesenchymal transition. Am. J. Physiol. Renal Physiol.2003;284:F911–924.[PubMed]
  • 110. Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall AThe small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell.1992;70:401–410.[PubMed]
  • 111. Nobes CD, Hall ARho, rac and cdc42 GTPases: regulators of actin structures, cell adhesion and motility. Biochem. Soc. Trans.1995;23:456–459.[PubMed]
  • 112. Sander EE, ten Klooster JP, van Delft S, van der Kammen RA, Collard JGRac downregulates Rho activity: reciprocal balance between both GTPases determines cellular morphology and migratory behavior. J. Cell Biol.1999;147:1009–1022.
  • 113. Zondag GC, et al Oncogenic Ras downregulates Rac activity, which leads to increased Rho activity and epithelial-mesenchymal transition. J. Cell Biol.2000;149:775–782.
  • 114. Cohnheim JÜber Entzündung und Eiterung. Virchows Arch.1867;40:1–79.[PubMed]
  • 115. Abe R, Donnelly SC, Peng T, Bucala R, Metz CNPeripheral blood fibrocytes: differentiation pathway and migration to wound sites. J. Immunol.2001;166:7556–7562.[PubMed]
  • 116. Huss RIsolation of primary and immortalized CD34-hematopoietic and mesenchymal stem cells from various sources. Stem Cells.2000;18:1–9.[PubMed]
  • 117. Bianco P, Robey PGMarrow stromal cells. J. Clin. Invest.2000;105:1663–1668.
  • 118. Bi LX, Simmons DJ, Hawkins HK, Cox RA, Mainous EGComparative morphology of the marrow sac. Anat. Rec.2000;260:410–415.[PubMed]
  • 119. Simmons DJThe in vivo role of bone marrow fibroblast-like stromal cells. Calcif. Tissue Int.1996;58:129–132.[PubMed]
  • 120. Weiss L, Geduldig UBarrier cells: stromal regulation of hematopoiesis and blood cell release in normal and stressed murine bone marrow. Blood.1991;78:975–990.[PubMed]
  • 121. Zhang J, et al Identification of the haematopoietic stem cell niche and control of the niche size. Nature.2003;425:836–841.[PubMed]
  • 122. Krause DS, et al Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell.2001;105:369–377.[PubMed]
  • 123. Huss R, Hong DS, McSweeney PA, Hoy CA, Deeg HJDifferentiation of canine bone marrow cells with hemopoietic characteristics from an adherent stromal cell precursor. Proc. Natl. Acad. Sci. U. S. A.1995;92:748–752.
  • 124. Huss RPerspectives on the morphology and biology of CD34-negative stem cells. J. Hematother.Stem Cell Res.2000;9:783–793.[PubMed]
  • 125. Garrett DM, Conrad GWFibroblast-like cells from embryonic chick cornea, heart, and skin are antigenically distinct. Dev. Biol.1979;70:50–70.[PubMed]
  • 126. Schor SL, Schor AMClonal heterogeneity in fibroblast phenotype: implications for the control of epithelial-mesenchymal interactions. Bioessays.1987;7:200–204.[PubMed]
  • 127. Müller GA, Rodemann HP. Characterization of human renal fibroblasts in health and disease. I. Immunophenotyping of cultured tubular epithelial cells and fibroblasts derived from kidneys with histologically proven interstitial fibrosis. Am. J. Kidney Dis.1991;17:680–683.[PubMed]
  • 128. Dugina V, Alexandrova A, Chaponnier C, Vasiliev J, Gabbiani GRat fibroblasts cultured from various organs exhibit differences in alpha-smooth muscle actin expression, cytoskeletal pattern, and adhesive structure organization. Exp. Cell. Res.1998;238:481–490.[PubMed]
  • 129. Alvarez RJ, et al Biosynthetic and proliferative characteristics of tubulointerstitial fibroblasts probed with paracrine cytokines. Kidney Int.1992;41:14–23.[PubMed]
  • 130. Chang HY, et al Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc. Natl. Acad. Sci. U. S. A.2002;99:12877–12882.
  • 131. Chilosi M, et al Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis. Am. J. Pathol.2003;162:1495–1502.
  • 132. Kalluri R, Danoff TM, Okada H, Neilson EGSusceptibility to anti-glomerular basement membrane disease and Goodpasture syndrome is linked to MHC class II genes and the emergence of T cell-mediated immunity in mice. J. Clin. Invest.1997;100:2263–2275.
  • 133. Cosgrove D, et al Collagen COL4A3 knockout: a mouse model for autosomal Alport syndrome. Genes Dev.1996;10:2981–2992.[PubMed]
  • 134. Anders H, Schlondorff DMurine models of renal disease: possibilities and problems in studies using mutant mice. Exp. Nephrol.2000;8:181–193.[PubMed]
  • 135. Janssen U, Phillips AO, Floege JRodent models of nephropathy associated with type II diabetes. J. Nephrol.1999;12:159–172.[PubMed]
  • 136. Diamond JR, Ricardo SD, Klahr SMechanisms of interstitial fibrosis in obstructive nephropathy. Semin. Nephrol.1998;18:594–602.[PubMed]
  • 137. Okada H, et al Progressive renal fibrosis in murine polycystic kidney disease: an immunohistochemical observation. Kidney Int.2000;58:587–597.[PubMed]
  • 138. Okada H, Strutz F, Danoff TM, Kalluri R, Neilson EGPossible mechanisms of renal fibrosis. Contrib. Nephrol.1996;118:147–154.[PubMed]
  • 139. Breen E, Falco VM, Absher M, Cutroneo KRSubpopulations of rat lung fibroblasts with different amounts of type I and type III collagen mRNAs. J. Biol. Chem.1990;265:6286–6290.[PubMed]
  • 140. Goldring SR, Stephenson ML, Downie E, Krane SM, Korn JHHeterogeneity in hormone responses and patterns of collagen synthesis in cloned dermal fibroblasts. J. Clin. Invest.1990;85:798–803.
  • 141. Jelaska A, Strehlow D, Korn JHFibroblast heterogeneity in physiological conditions and fibrotic disease. Springer Semin. Immunopathol.1999;21:385–395.[PubMed]
  • 142. Rossert RA, Chen SS, Eberspaecher H, Smith CN, De Crombrugghe BIdentification of a minimal sequence of the mouse pro-a1(I) collagen promoter that confers high-level osteoblast expression in transgenic mice and that binds a protein selectively present in osteoblasts. Proc. Natl. Acad. Sci. U. S. A.1996;93:1027–1031.
  • 143. Zeisberg M, Strutz F, Muller GARole of fibroblast activation in inducing interstitial fibrosis. J. Nephrol.2000;13(Suppl. 3):S111–S120.[PubMed]
  • 144. Serini G, Gabbiani GMechanisms of myofibroblast activity and phenotypic modulation. Exp. Cell Res.1999;250:273–283.[PubMed]
  • 145. Tang WW, et al Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis. Am. J. Pathol.1996;148:1169–1180.
  • 146. Ng YY, et al Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Kidney Int.1998;54:864–876.[PubMed]
  • 147. Eyden BThe myofibroblast: an assessment of controversial issues and a definition useful in diagnosis and research. Ultrastruct. Pathol.2001;25:39–50.[PubMed]
  • 148. Yang J, et al Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy. J. Clin. Invest.2002;110:1525–1538. doi:10.1172/JCI200216219.
  • 149. Yang J, Liu YBlockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis. J. Am. Soc. Nephrol.2002;13:96–107.[PubMed]
  • 150. Zeisberg M, et al Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am. J. Physiol. Renal Physiol.2003;285:F1060–F1067.[PubMed]
  • 151. Kalluri R, Zeisberg MExploring the connection between chronic renal fibrosis and bone morphogenic protein-7. Histol. Histopathol.2003;18:217–224.[PubMed]
  • 152. Morrissey J, et al Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function. J. Am. Soc. Nephrol.2002;13(Suppl. 1):S14–S21.[PubMed]
  • 153. Wang S, et al Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy. Kidney Int.2003;63:2037–2049.[PubMed]
  • 154. Gould SJ, Vrba ESExaptation — a missing term in the science of form. Paleobiology.1982;8:4–15.[PubMed]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.