Scar wars: mapping the fate of epithelial–mesenchymal–myofibroblast transition
2011; Elsevier BV; Volume: 80; Issue: 1 Linguagem: Inglês
10.1038/ki.2011.77
ISSN1523-1755
AutoresSusan E. Quaggin, András Kapùs,
Tópico(s)Tissue Engineering and Regenerative Medicine
ResumoThe hypothesis that epithelial–mesenchymal transition (EMT) might be a contributor to the accumulation of fibroblasts and myofibroblasts (MFs) in the kidney during fibrogenesis was postulated 15 years ago. This paradigm offered an elegant explanation of how the loss of epithelial functions is coupled to the gain of deleterious mesenchymal functions; for example, excessive matrix deposition. Moreover, it interpreted chronic kidney disease in a developmental context: because the tubular epithelium originates from the metanephric mesenchyme, EMT can be viewed as a dedifferentiation process in response to injury, which might serve healing or—if dysregulated—might facilitate fibrosis. Several observations support the role of EMT in renal fibrosis: (1) Tubular cells can transform to fibroblasts and MFs in vitro. (2) Histological ‘snapshots’ reveal the coexistence of epithelial and mesenchymal markers in transitioning tubular cells in fibrosis models and human kidney diseases. (3) Early lineage-tracing experiments detected mesenchymal markers in the genetically tagged epithelium. However, the paradigm has been recently challenged; new fate-mapping studies found no evidence for the expression of (myo)fibroblast markers in the epithelium during fibrogenesis. This review summarizes the key findings and caveats, aiming at a balanced view, which neither overestimates the role of the epithelium in MF generation nor denies the importance of epithelial plasticity in fibrogenesis. The hypothesis that epithelial–mesenchymal transition (EMT) might be a contributor to the accumulation of fibroblasts and myofibroblasts (MFs) in the kidney during fibrogenesis was postulated 15 years ago. This paradigm offered an elegant explanation of how the loss of epithelial functions is coupled to the gain of deleterious mesenchymal functions; for example, excessive matrix deposition. Moreover, it interpreted chronic kidney disease in a developmental context: because the tubular epithelium originates from the metanephric mesenchyme, EMT can be viewed as a dedifferentiation process in response to injury, which might serve healing or—if dysregulated—might facilitate fibrosis. Several observations support the role of EMT in renal fibrosis: (1) Tubular cells can transform to fibroblasts and MFs in vitro. (2) Histological ‘snapshots’ reveal the coexistence of epithelial and mesenchymal markers in transitioning tubular cells in fibrosis models and human kidney diseases. (3) Early lineage-tracing experiments detected mesenchymal markers in the genetically tagged epithelium. However, the paradigm has been recently challenged; new fate-mapping studies found no evidence for the expression of (myo)fibroblast markers in the epithelium during fibrogenesis. This review summarizes the key findings and caveats, aiming at a balanced view, which neither overestimates the role of the epithelium in MF generation nor denies the importance of epithelial plasticity in fibrogenesis. In his thought-provoking review,1.Wynn T.A. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases.J Clin Invest. 2007; 117: 524-529Crossref PubMed Scopus (524) Google Scholar Thomas Winn called the world's attention to the underappreciated fact that ≈45% of all deaths in the western world can be attributed to some form of tissue or organ fibrosis. Kidney diseases signify an important set within this category, as essentially all chronic nephropathies, irrespective of their etiology, culminate in a final common pathological pathway characterized by glomerulosclerosis and/or tubulointerstitial fibrosis.2.Eddy A.A. Progression in chronic kidney disease.Adv Chronic Kidney Dis. 2005; 12: 353-365Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 3.Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics.Kidney Int. 2006; 69: 213-217Abstract Full Text Full Text PDF PubMed Scopus (480) Google Scholar Organ fibrosis is generally viewed as a dysregulated (and thus failed) healing process provoked by chronic or repetitive injury of the epithelium or endothelium of the affected parenchymal organs.4.Wynn T.A. Cellular and molecular mechanisms of fibrosis.J Pathol. 2008; 214: 199-210Crossref PubMed Scopus (1298) Google Scholar The key feature of the process is the tissue accumulation of fibroblasts and their contractile and potentially invasive subtype, the myofibroblasts (MFs), hallmarked by the expression of α-smooth muscle actin (SMA). These cell types, stimulated by a variety of fibrogenic cytokines (predominantly by transforming growth factor-β1,5.Bottinger E.P. TGF-beta in renal injury and disease.Semin Nephrol. 2007; 27: 309-320Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar and other humoral and mechanical inputs emanating from the injured environment6.Leask A. Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation.Circ Res. 2010; 106: 1675-1680Crossref PubMed Scopus (237) Google Scholar, 7.Nishimura S.L. Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders.Am J Pathol. 2009; 175: 1362-1370Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 8.Hinz B. Tissue stiffness, latent TGF-beta1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosis.Curr Rheumatol Rep. 2009; 11: 120-126Crossref PubMed Scopus (103) Google Scholar lay down an excessive amount of extracellular matrix (ECM), which ultimately leads to the destruction of the normal tissue architecture. In short, the epithelium is gradually replaced by mesenchymal cells and fibrous scar tissue. Given this scenario, it is understandable that the question of where the accumulating fibroblasts (and MFs) originate from has become a major focus in fibrosis research. Although this problem is not yet resolved, evidence has been accumulating that the sources are multiple and, depending on the organ (for example, lung, liver, lens, or kidney) and the underlying pathology, both proliferation and transformation of local cells, as well as population of the affected organ by external fibroblast progenitors may contribute to the process.9.Grande M.T. Lopez-Novoa J.M. Fibroblast activation and myofibroblast generation in obstructive nephropathy.Nat Rev Nephrol. 2009; 5: 319-328Crossref PubMed Scopus (103) Google Scholar Accordingly, the sources may include local interstitial fibroblasts,10.Strutz F. Zeisberg M. Renal fibroblasts and myofibroblasts in chronic kidney disease.J Am Soc Nephrol. 2006; 17: 2992-2998Crossref PubMed Scopus (127) Google Scholar pericytes (or perivascular fibroblasts),11.Lin S.L. Kisseleva T. Brenner D.A. Duffield J.S. Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney.Am J Pathol. 2008; 173: 1617-1627Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar, 12.Humphreys B.D. Lin S.L. Kobayashi A. et al.Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis.Am J Pathol. 2010; 176: 85-97Abstract Full Text Full Text PDF PubMed Scopus (474) Google Scholar local mesenchymal stem cells, bone marrow-derived-circulating fibrocytes13.Keeley E.C. Mehrad B. Strieter R.M. Fibrocytes: bringing new insights into mechanisms of inflammation and fibrosis.Int J Biochem Cell Biol. 2010; 42: 535-542Crossref PubMed Scopus (44) Google Scholar (Cd45 and collagen-1-positive cells), the endothelium,14.Zeisberg E.M. Potenta S.E. Sugimoto H. Zeisberg M. Kalluri R. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition.J Am Soc Nephrol. 2008; 19: 2282-2287Crossref PubMed Scopus (289) Google Scholar, 15.Li J. Bertram J.F. Review: endothelial-myofibroblast transition, a new player in diabetic renal fibrosis.Nephrology (Carlton). 2010; 15: 507-512Crossref PubMed Scopus (30) Google Scholar and last but not least, the injured epithelium itself 16.Iwano M. Plieth D. Danoff T.M. Xue C. Okada H. Neilson E.G. Evidence that fibroblasts derive from epithelium during tissue fibrosis.J Clin Invest. 2002; 110: 341-350Crossref PubMed Scopus (0) Google Scholar, 17.Liu Y. New insights into epithelial-mesenchymal transition in kidney fibrosis.J Am Soc Nephrol. 2010; 21: 212-222Crossref PubMed Scopus (310) Google Scholar In this short overview, we will concentrate on the latter mechanism, that is, on the concept that during fibrogenesis, fibroblasts can be generated from the epithelium through the process of epithelial–mesenchymal transition (EMT). In 1995, aiming at finding distinguishing markers for fibroblasts, Strutz et al.18.Strutz F. Okada H. Lo C.W. et al.Identification and characterization of a fibroblast marker: FSP1.J Cell Biol. 1995; 130: 393-405Crossref PubMed Scopus (593) Google Scholar used subtractive hybridization between murine fibroblasts and isogenic epithelium, and identified fibroblast-specific protein 1 (FSP1, also called S1004A) as one of the few gene products that was expressed in fibroblasts but not in mesangial or epithelial cells. Generation of an anti-FSP1 serum provided a powerful tool to address the origins of fibroblasts in fibrosing tissues. Using this reagent, and thereby discovering that a portion of tubular cells became FSP1 positive during immune-induced fibrogenesis, the Neilson group made an extremely careful (and pioneering) assumption: ‘This pattern of anti-FSP1 staining during tissue fibrosis suggests, as a hypothesis, that fibroblasts in some cases arise, as needed, from the local conversion of epithelium’.18.Strutz F. Okada H. Lo C.W. et al.Identification and characterization of a fibroblast marker: FSP1.J Cell Biol. 1995; 130: 393-405Crossref PubMed Scopus (593) Google Scholar This sentence signified the birth of a new paradigm: the role of local EMT in fibrogenesis (Figure 1). This concept is both powerful and intellectually appealing for two major reasons. First, it offers a direct link between the loss of epithelial functions (for example, absorption and secretion) and the gain of deleterious mesenchymal functions (enhanced ECM production). Second, it roots in and is consistent with the developmental biology of the kidney in that the tubular epithelium is a secondary epithelium, which differentiates from the metanephric mesenchyme through the process of mesenchymal–epithelial transition.19.Hay E.D. Zuk A. Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced.Am J Kidney Dis. 1995; 26: 678-690Abstract Full Text PDF PubMed Scopus (270) Google Scholar In this sense, the response to epithelial injury could be interpreted as the activation of a dedifferentiation program, which might either lead to healing through an epithelial–mesenchymal–epithelial cycle20.Ishibe S. Cantley L.G. Epithelial-mesenchymal-epithelial cycling in kidney repair.Curr Opin Nephrol Hypertens. 2008; 17: 379-385Crossref PubMed Scopus (36) Google Scholar or it might result in fibrosis through EMT.21.Kalluri R. Neilson E.G. Epithelial-mesenchymal transition and its implications for fibrosis.J Clin Invest. 2003; 112: 1776-1784Crossref PubMed Scopus (1223) Google Scholar Prompted by this exciting intellectual framework, a large number of researchers set to work to establish the potential role of EMT in fibrogenesis. In the past 15 years, several hundred papers have been published, which provided observational and experimental support for the possibility that EMT is a contributor to organ fibrosis, in general, and tubulointerstitial fibrosis, in particular. (For excellent reviews, see refs 1.Wynn T.A. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases.J Clin Invest. 2007; 117: 524-529Crossref PubMed Scopus (524) Google Scholar,9.Grande M.T. Lopez-Novoa J.M. Fibroblast activation and myofibroblast generation in obstructive nephropathy.Nat Rev Nephrol. 2009; 5: 319-328Crossref PubMed Scopus (103) Google Scholar,17.Liu Y. New insights into epithelial-mesenchymal transition in kidney fibrosis.J Am Soc Nephrol. 2010; 21: 212-222Crossref PubMed Scopus (310) Google Scholar,21.Kalluri R. Neilson E.G. Epithelial-mesenchymal transition and its implications for fibrosis.J Clin Invest. 2003; 112: 1776-1784Crossref PubMed Scopus (1223) Google Scholar, 22.Zeisberg M. Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis.J Mol Med. 2004; 82: 175-181Crossref PubMed Scopus (303) Google Scholar, 23.Kalluri R. Weinberg R.A. The basics of epithelial-mesenchymal transition.J Clin Invest. 2009; 119: 1420-1428Crossref PubMed Scopus (2261) Google Scholar, 24.Thiery J.P. Acloque H. Huang R.Y. Nieto M.A. Epithelial-mesenchymal transitions in development and disease.Cell. 2009; 139: 871-890Abstract Full Text Full Text PDF PubMed Scopus (2853) Google Scholar, 25.Zeisberg M. Neilson E.G. Biomarkers for epithelial-mesenchymal transitions.J Clin Invest. 2009; 119: 1429-1437Crossref PubMed Scopus (659) Google Scholar, 26.Rastaldi M.P. Epithelial-mesenchymal transition and its implications for the development of renal tubulointerstitial fibrosis.J Nephrol. 2006; 19: 407-412PubMed Google Scholar, 27.Strutz F. Pathogenesis of tubulointerstitial fibrosis in chronic allograft dysfunction.Clin Transplant. 2009; 23: 26-32Crossref PubMed Google Scholar.) These supportive arguments can be broadly classified into four categories: (1) Demonstration that tubular and other epithelial cells can indeed transform into fibroblasts and MFs when cultured and challenged in vitro. There is no doubt that epithelial cells possess this potentiality as a part of their repertoire in response to injury. (2)28.Fan J.M. Ng Y.Y. Hill P.A. et al.Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro.Kidney Int. 1999; 56: 1455-1467Abstract Full Text Full Text PDF PubMed Scopus (369) Google Scholar, 29.Yang J. Liu Y. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis.Am J Pathol. 2001; 159: 1465-1475Abstract Full Text Full Text PDF PubMed Google Scholar, 30.Masszi A. Di Ciano C. Sirokmany G. 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-F924Crossref PubMed Google Scholar ‘Snapshots’ of molecular markers and events characteristic of EMT, as detected in tubular cells in vivo, during clinical or experimental fibrosis. These observations can be divided into two sets. The first demonstrates downregulation (partial loss) of epithelial markers (for example, E-cadherin) and concomitant upregulation of mesenchymal markers (for example, FSP1) in the injured (transitioning) epithelium. The second documents changes in the expression or activity of transcription factors, reflecting a profound transcriptional reprogramming, which is consistent with the reported transcriptional signature of EMT (see next section). (3) Fate-mapping or lineage-tracing experiments, in which the epithelium is genetically tagged, and thus cells of epithelial origin can be identified throughout the disease process. Using one version of this approach (see below) Iwano et al.,16.Iwano M. Plieth D. Danoff T.M. Xue C. Okada H. Neilson E.G. Evidence that fibroblasts derive from epithelium during tissue fibrosis.J Clin Invest. 2002; 110: 341-350Crossref PubMed Scopus (0) Google Scholar concluded that 36% of FSP1+ cells (that is, fibroblasts) originated from the epithelium during unilateral ureteral obstruction (UUO) as a model of kidney fibrosis. Qualitatively similar findings were obtained in lung,31.Kim K.K. Kugler M.C. Wolters P.J. et al.Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix.Proc Natl Acad Sci USA. 2006; 103: 13180-13185Crossref PubMed Scopus (549) Google Scholar, 32.Kim K.K. Wei Y. Szekeres C. et al.Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis.J Clin Invest. 2009; 119: 213-224PubMed Google Scholar, 33.Tanjore H. Xu X.C. Polosukhin V.V. et al.Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis.Am J Respir Crit Care Med. 2009; 180: 657-665Crossref PubMed Scopus (140) Google Scholar liver,34.Zeisberg M. Yang C. Martino M. et al.Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition.J Biol Chem. 2007; 282: 23337-23347Crossref PubMed Scopus (427) Google Scholar and intestinal models.35.Flier S.N. Tanjore H. Kokkotou E.G. Sugimoto H. Zeisberg M. Kalluri R. Identification of epithelial to mesenchymal transition as a novel source of fibroblasts in intestinal fibrosis.J Biol Chem. 2010Crossref Scopus (0) Google Scholar (4) Finally, recent data suggest that therapeutic approaches targeted to suppress EMT may lessen fibrosis,36.Oba S. Kumano S. Suzuki E. et al.miR-200b precursor can ameliorate renal tubulointerstitial fibrosis.PLoS One. 2010; 5: e13614Crossref PubMed Scopus (58) Google Scholar, 37.Kang Y.S. Li Y. Dai C. Kiss L.P. Wu C. Liu Y. Inhibition of integrin-linked kinase blocks podocyte epithelial-mesenchymal transition and ameliorates proteinuria.Kidney Int. 2010; 78: 363-373Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar and conversely, antifibrotic interventions can mitigate the signs of EMT.38Kaneyama T. Kobayashi S. Aoyagi D. Ehara T. Tranilast modulates fibrosis, epithelial-mesenchymal transition and peritubular capillary injury in unilateral ureteral obstruction rats.Pathology. 2010; 42: 564-573Crossref PubMed Scopus (17) Google Scholar, 39.Zeisberg M. Hanai J. Sugimoto H. et al.BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury.Nat Med. 2003; 9: 964-968Crossref PubMed Scopus (775) Google Scholar, 40.Yu M.A. Shin K.S. Kim J.H. et al.HGF and BMP-7 ameliorate high glucose-induced epithelial-to-mesenchymal transition of peritoneal mesothelium.J Am Soc Nephrol. 2009; 20: 567-581Crossref PubMed Scopus (58) Google Scholar Although certainly compelling, the concept of fibrogenic EMT has been recently challenged. Although the presence and role of EMT in lung fibrosis appear to be generally accepted,41.Chapman H.A. Epithelial-mesenchymal interactions in pulmonary fibrosis.Annu Rev Physiol. 2011; 73: 413-435Crossref PubMed Scopus (108) Google Scholar doubts have been raised in the context of the kidney12.Humphreys B.D. Lin S.L. Kobayashi A. et al.Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis.Am J Pathol. 2010; 176: 85-97Abstract Full Text Full Text PDF PubMed Scopus (474) Google Scholar, 42.Li L. Zepeda-Orozco D. Black R. Lin F. Autophagy is a component of epithelial cell fate in obstructive uropathy.Am J Pathol. 2010; 176: 1767-1778Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 43.Koesters R. Kaissling B. Lehir M. et al.Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells.Am J Pathol. 2010; 177: 632-643Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar and the liver44.Taura K. Miura K. Iwaisako K. et al.Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice.Hepatology. 2010; 51: 1027-1036Crossref PubMed Scopus (144) Google Scholar, 45.Scholten D. Osterreicher C.H. Scholten A. et al.Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice.Gastroenterology. 2010; 139: 987-998Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar on the basis of the results of new fate-mapping experiments (Table 1). For example, using different epithelial and mesenchymal tags (see below), Humphreys et al.12.Humphreys B.D. Lin S.L. Kobayashi A. et al.Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis.Am J Pathol. 2010; 176: 85-97Abstract Full Text Full Text PDF PubMed Scopus (474) Google Scholar found no evidence of EMT during UUO or ischemic injury, postulating that the epithelium did not give rise to any SMA+ or even FSP1+ cells. Instead they proposed that (myo)fibroblasts were exclusively derived from local pericytes.Table 1Lineage tracing studies assessing the presence of EMT during fibrogenesisOrgan cell typeDriver (Promoter)/Reporter systemFate markerDisease modelFibrosis markerConclusion with regards to EMT, remarksRefLUNG Alveolar epitheliumSurfactant (SCP)-rTA/tetO-CMV-Cre ROSA26LacZβ-galactosidase /X-galAd-TGFβ1-induced pulmonary fibrosisSMA, vimentinYes31.Kim K.K. Kugler M.C. Wolters P.J. et al.Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix.Proc Natl Acad Sci USA. 2006; 103: 13180-13185Crossref PubMed Scopus (549) Google Scholar Alveolar epitheliumSurfactant (SCP)-rTA/tetO-CMV-Cre ZEGGFPBleomycin-induced pulmonary fibrosisSMA, vimentin, procollagen IYesEpithelial-specific deletion of α3 integrin prevented EMT32.Kim K.K. Wei Y. Szekeres C. et al.Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis.J Clin Invest. 2009; 119: 213-224PubMed Google Scholar Alveolar epitheliumSCP-Cre/ROSA26LacZS100A4-GFPS1004A-Creβ-galactosidase/anti- β-gal AB GFPBleomycin-induced pulmonary fibrosisFSP1SMAGFP (SFP1 promoter)Yes33.Tanjore H. Xu X.C. Polosukhin V.V. et al.Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis.Am J Respir Crit Care Med. 2009; 180: 657-665Crossref PubMed Scopus (140) Google ScholarKIDNEY Tubular epitheliumβ-glutamyl transferase -Cre/ROSA26LacZβ-galactosidase/anti- β-gal ABUUOFSP1HSP47SMAYes16.Iwano M. Plieth D. Danoff T.M. Xue C. Okada H. Neilson E.G. Evidence that fibroblasts derive from epithelium during tissue fibrosis.J Clin Invest. 2002; 110: 341-350Crossref PubMed Scopus (0) Google Scholar Tubular epitheliumSix2-GFP-Cre/ROSA26LacZ or Z/Red (CMV/β-actin)HoxB7-Cre/ROSA26LacZ or Z/Red (CMV/β-actin)β-galactosidase /X-galRFPβ-galactosidase/X-galRFPUUO Ischemia-reperfusionSMAFSP1NoMesenchymal cells were also genetically tagged with FOXD112.Humphreys B.D. Lin S.L. Kobayashi A. et al.Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis.Am J Pathol. 2010; 176: 85-97Abstract Full Text Full Text PDF PubMed Scopus (474) Google Scholar Tubular and ureteral epitheliumKsp-Cre/ROSA26-EYFPEYFPUUOE-cadherinFSP1SMANo42.Li L. Zepeda-Orozco D. Black R. Lin F. Autophagy is a component of epithelial cell fate in obstructive uropathy.Am J Pathol. 2010; 176: 1767-1778Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Tubular epitheliumPax8rtTA/LC1/ROSA26R/tet-o-TGF-β1β-galactosidase/X-galTetracyclin-inducible expression of active TGFβ in tubular cellsDirectly: collagen I In parallel but not with labeled epithelium: FSP1, SMANo43.Koesters R. Kaissling B. Lehir M. et al.Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells.Am J Pathol. 2010; 177: 632-643Abstract Full Text Full Text PDF PubMed Scopus (112) Google ScholarLIVER HepatocytesAlb-Cre/ROSA26LacZβ-galactosidase/anti- β-gal ABCCL4-induced liver fibrosisE-cadherinFSP1SMAYesSmad7 prevented EMT34.Zeisberg M. Yang C. Martino M. et al.Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition.J Biol Chem. 2007; 282: 23337-23347Crossref PubMed Scopus (427) Google Scholar HepatocytesAlb-Cre/ROSA26LacZ α1(I) collagen promoter-GFPβ-galactosidase/anti- β-gal ABCCL4-induced liver fibrosisSMAFSP1No collagen promoter was not activated in hepatocytes (GFP)44.Taura K. Miura K. Iwaisako K. et al.Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice.Hepatology. 2010; 51: 1027-1036Crossref PubMed Scopus (144) Google Scholar CholangiocytesCytokeratin 19-Cre-ErtYFP/ROSA26YFPYFPBile duct ligationCCL4-induced fibrosisSMADesminFSP1NoPotential activation of the FSP1 promoter FSP1-Cre/Rosa26/YFP was also tested. MET was also assessed using GFAP-Cre/Rosa26/GFP and Col-α2(I)-YFP animals45.Scholten D. Osterreicher C.H. Scholten A. et al.Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice.Gastroenterology. 2010; 139: 987-998Abstract Full Text Full Text PDF PubMed Scopus (103) Google ScholarGUT Intestinal epitheliumVillin-Cre/ROSA26LacZβ-galactosidase/anti-β-gal AB2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colonic inflammation (Crohn's disease)E-cadherin FSP1Yes35.Flier S.N. Tanjore H. Kokkotou E.G. Sugimoto H. Zeisberg M. Kalluri R. Identification of epithelial to mesenchymal transition as a novel source of fibroblasts in intestinal fibrosis.J Biol Chem. 2010Crossref Scopus (0) Google ScholarFate-mapping studies have given discordant results about the presence of EMT in organ fibrosis. The discrepancies might be due to different methods to define and detect EMT in various disease models. Systematic comparisons of such variables as well as the assessment of potential differences in the background strains (a factor not easily determined in multiple transgenic animals) are warranted to establish the contribution of EMT to fibrogenesis. FSP1, fibroblast-specific protein 1; UUO, unilateral ureteral obstruction. Open table in a new tab Fate-mapping studies have given discordant results about the presence of EMT in organ fibrosis. The discrepancies might be due to different methods to define and detect EMT in various disease models. Systematic comparisons of such variables as well as the assessment of potential differences in the background strains (a factor not easily determined in multiple transgenic animals) are warranted to establish the contribution of EMT to fibrogenesis. FSP1, fibroblast-specific protein 1; UUO, unilateral ureteral obstruction. These opposite views have led to an ongoing debate. The arguments for and against the presence and participation of EMT have been eloquently summarized in a recent issue of JASN46.Zeisberg M. Duffield J.S. Resolved: EMT produces fibroblasts in the kidney.J Am Soc Nephrol. 2010; 21: 1247-1253Crossref PubMed Scopus (132) Google Scholar by Michael Zeisberg and Jeremy Duffield, respectively, two excellent representatives of each opinion, whose studies had a major role in the very foundation of the differing viewpoints. Our short summary cannot and does not aspire to settle the debate or to take sides; its goal is to highlight a few facts and considerations, which may help to better define the fundamental concepts in question and to point out the strengths, as well as the potential pitfalls and limitations of each of the approaches used to address the problem. Clearly, having a meaningful debate will depend upon (1) the criteria that one uses to define EMT; (2) the particular disease entity or experimental model in which fibrosis and EMT are studied; and (3) the methods used to detect EMT. We hope that this overview will facilitate the design of future studies and will contribute to the emergence of a balanced view, which avoids both the overestimation of the role of EMT in MF generation and the denial of the presence and importance of epithelial plasticity during fibrogenesis. EMT is defined as a phenotypic change, characterized by the loss of apico-basal polarity, polygonal cell shape, and epithelial intercellular contacts (tight and adherens junctions), accompanied by the acquisition of elongated (mesenchymal) shape, increased motility, and contractility.24.Thiery J.P. Acloque H. Huang R.Y. Nieto M.A. Epithelial-mesenchymal transitions in development and disease.Cell. 2009; 139: 871-890Abstract Full Text Full Text PDF PubMed Scopus (2853) Google Scholar, 47.Xu J. Lamouille S. Derynck R. TGF-beta-induced epithelial to mesenchymal transition.Cell Res. 2009; 19: 156-172Crossref PubMed Scopus (599) Google Scholar, 48.Thiery J.P. Epithelial-mesenchymal transitions in development and pathologies.Curr Opin Cell Biol. 2003; 15: 740-746Crossref PubMed Scopus (1019) Google Scholar, 49.Yilmaz M. Christofori G. EMT, the cytoskeleton, and cancer cell invasion.Cancer Metastasis Rev. 2009; 28: 15-33Crossref PubMed Scopus (440) Google Scholar The process involves dramatic remodeling of the cytoskeleton, which usually manifests as a cytokeratin-to-vimentin switch in the intermediate filaments and restructuring of microfilaments, with a loss of the junctional F-actin belt and an increase in stress fibers and/or peripheral F-actin branches. The basic theme of this profound form of epithelial plasticity can be supplemented with other attributes, such as excessive production of ECM, SMA expression, invasiveness, and reduction in apoptosis. According to the biological context in which EMT occurs as well as the presence of some specific attributes, the International EMT Association (TEMTIA) accepted the suggestion that EMT be classified into three subtypes.23.Kalluri R. Weinberg R.A. The basics of epithelial-mesenchymal transition.J Clin Invest. 2009; 119: 1420-1428Crossref PubMed Scopus (2261) Google Scholar, 25.Zeisberg M. Neilson E.G. Biomarkers for epithelial-mesenchymal transitions.J Clin Invest. 2009; 119: 1429-1437Crossref PubMed Scopus (659) Google Scholar, 50.Acloque H. Adams M.S. Fishwick K. Bronner-Fraser M. Nieto M.A. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease.J Clin Invest. 2009; 119: 1438-1449Crossref P
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