Evidence that fibroblasts derive from epithelium during tissue fibrosis.
Journal: 2002/September - Journal of Clinical Investigation
ISSN: 0021-9738
Abstract:
Interstitial fibroblasts are principal effector cells of organ fibrosis in kidneys, lungs, and liver. While some view fibroblasts in adult tissues as nothing more than primitive mesenchymal cells surviving embryologic development, they differ from mesenchymal cells in their unique expression of fibroblast-specific protein-1 (FSP1). This difference raises questions about their origin. Using bone marrow chimeras and transgenic reporter mice, we show here that interstitial kidney fibroblasts derive from two sources. A small number of FSP1(+), CD34(-) fibroblasts migrate to normal interstitial spaces from bone marrow. More surprisingly, however, FSP1(+) fibroblasts also arise in large numbers by local epithelial-mesenchymal transition (EMT) during renal fibrogenesis. Both populations of fibroblasts express collagen type I and expand by cell division during tissue fibrosis. Our findings suggest that a substantial number of organ fibroblasts appear through a novel reversal in the direction of epithelial cell fate. As a general mechanism, this change in fate highlights the potential plasticity of differentiated cells in adult tissues under pathologic conditions.
Relations:
Content
Citations
(629)
References
(62)
Diseases
(1)
Conditions
(1)
Chemicals
(5)
Genes
(1)
Organisms
(7)
Processes
(2)
Anatomy
(6)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
J Clin Invest 110(3): 341-350

Evidence that fibroblasts derive from epithelium during tissue fibrosis

Department of Medicine, and Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA GlaxoSmithKline, Philadelphia, Pennsylvania, USA Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Department of Nephrology, Saitama Medical College, Irumagun, Japan
Address correspondence to: Eric G. Neilson, Department of Medicine, D-3100 Medical Center North, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2358, USA. Phone: (615) 322-3146; Fax: (615) 343-9391; E-mail: ude.tlibrednaV@noslieN.cirE.
Address correspondence to: Eric G. Neilson, Department of Medicine, D-3100 Medical Center North, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2358, USA. Phone: (615) 322-3146; Fax: (615) 343-9391; E-mail: ude.tlibrednaV@noslieN.cirE.
Received 2002 Mar 25; Accepted 2002 Jun 11.

Abstract

Interstitial fibroblasts are principal effector cells of organ fibrosis in kidneys, lungs, and liver. While some view fibroblasts in adult tissues as nothing more than primitive mesenchymal cells surviving embryologic development, they differ from mesenchymal cells in their unique expression of fibroblast-specific protein-1 (FSP1). This difference raises questions about their origin. Using bone marrow chimeras and transgenic reporter mice, we show here that interstitial kidney fibroblasts derive from two sources. A small number of FSP1, CD34 fibroblasts migrate to normal interstitial spaces from bone marrow. More surprisingly, however, FSP1 fibroblasts also arise in large numbers by local epithelial-mesenchymal transition (EMT) during renal fibrogenesis. Both populations of fibroblasts express collagen type I and expand by cell division during tissue fibrosis. Our findings suggest that a substantial number of organ fibroblasts appear through a novel reversal in the direction of epithelial cell fate. As a general mechanism, this change in fate highlights the potential plasticity of differentiated cells in adult tissues under pathologic conditions.

Abstract

Acknowledgments

We thank Brigid Hogan and Harold Moses at Vanderbilt University for helpful comments during the early preparation of this manuscript. Part of this work was presented in abstract form at the annual Meeting of the American Society of Nephrology in October, 2000. E.G. Neilson is supported in part by NIH grants DK-46282 and HL-68121.

Acknowledgments

Footnotes

See the related Commentary beginning on page 305.

Masayuki Iwano and David Plieth contributed equally to this work.

Conflict of interest: No conflict of interest has been declared.

Nonstandard abbreviations used: marrow stromal cells (MSCs); epithelial-mesenchymal transition (EMT); fibroblast-specific protein-1 (FSP1); green fluorescent protein (GFP); unilateral ureteral obstruction (UUO); bone marrow lining cell (BMLC).

Footnotes

References

  • 1. Peifer M, McEwen DGThe ballet of morphogenesis: unveiling the hidden choreographers. Cell. 2002;109:271–274.[PubMed][Google Scholar]
  • 2. Watt FM, Hogan BLMOut of Eden: stem cells and their niches. Science. 2000;287:1427–1430.[PubMed][Google Scholar]
  • 3. Spradling A, Drummond-Barbosa D, Kai TStem cells find their niche. Nature. 2001;414:98–104.[PubMed][Google Scholar]
  • 4. Weissman ILTranslating stem and progenitor cell biology to the clinic: barriers and opportunities. Science. 2000;287:1442–1445.[PubMed][Google Scholar]
  • 5. Blau HM, Brazelton TR, Weimann JMThe evolving concept of a stem cell: entity or function? Cell. 2001;105:829–841.[PubMed][Google Scholar]
  • 6. Prockop DJMarrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;276:71–74.[PubMed][Google Scholar]
  • 7. Strutz F, et al Identification and characterization of a fibroblast marker: FSP1. J Cell Biol. 1995;130:393–405.[Google Scholar]
  • 8. 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][Google Scholar]
  • 9. Bucala R, Spiegel LA, Chesney J, Hogan N, Cerami ACirculating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med. 1994;1:71–81.[Google Scholar]
  • 10. Friedenstein AJ, et al Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol. 1974;2:83–92.[PubMed][Google Scholar]
  • 11. 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][Google Scholar]
  • 12. Krause DS, et al Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 2001;105:369–377.[PubMed][Google Scholar]
  • 13. Bianco P, Robey PGMarrow stromal cells. J Clin Invest. 2000;105:1663–1668.[Google Scholar]
  • 14. Hay ED, Zuk ATransformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. Am J Kidney Dis. 1995;26:678–690.[PubMed][Google Scholar]
  • 15. Tam PP, Behringer RRMouse gastrulation: the formation of a mammalian body plan. Mech Dev. 1997;68:3–25.[PubMed][Google Scholar]
  • 16. Boyer B, Valles AM, Edme NInduction and regulation of epithelial-mesenchymal transitions. Biochem Pharmacol. 2000;60:1091–1099.[PubMed][Google Scholar]
  • 17. Ng YY, et al Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Kidney Int. 1998;54:864–876.[PubMed][Google Scholar]
  • 18. Okada H, Danoff TM, Kalluri R, Neilson EGThe early role of FSP1 in epithelial-mesenchymal transformation. Am J Physiol. 1997;273:563–574.[PubMed][Google Scholar]
  • 19. Okada H, et al Progressive renal fibrosis in murine polycystic kidney disease: an immunohistochemical observation. Kidney Int. 2000;58:587–597.[PubMed][Google Scholar]
  • 20. Zeisberg M, et al Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiation. Am J Pathol. 2001;159:1313–1321.[Google Scholar]
  • 21. Zavadil J, et al Genetic programs of epithelial cell plasticity directed by transforming growth factor-beta. Proc Natl Acad Sci USA. 2001;98:6686–6691.[Google Scholar]
  • 22. Strutz F, et al Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int. 2002;61:1714–1728.[PubMed][Google Scholar]
  • 23. 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.[Google Scholar]
  • 24. Cano A, et al The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2:76–83.[PubMed][Google Scholar]
  • 25. Okada H, et al Novel cis-acting elements in the FSP1 gene regulate fibroblast-specific transcription. Am J Physiol. 1998;275:306–314.[PubMed][Google Scholar]
  • 26. Gu H, Zou YR, Rajewsky KIndependent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting. Cell. 1993;73:1155–1164.[PubMed][Google Scholar]
  • 27. Schaffner DL, et al Targeting of the rasT24 oncogene to the proximal convoluted tubules in transgenic mice results in hyperplasia and polycystic kidneys. Am J Pathol. 1993;142:1051–1060.[Google Scholar]
  • 28. Makino Y, et al Impaired T cell function in RANTES-deficient mice. Clin Immunol. 2002;102:302–309.[PubMed][Google Scholar]
  • 29. Soriano PGeneralized LacZ expression with the ROSA26 Cre reporter strain. Nat Genet. 1999;21:70–71.[PubMed][Google Scholar]
  • 30. Moriyama T, et al Up-regulation of HSP47 in the mouse kidneys with unilateral ureteral obstruction. Kidney Int. 1998;54:110–119.[PubMed][Google Scholar]
  • 31. Klahr S, Morrissey JThe role of growth factors, cytokines, and vasoactive compounds in obstructive nephropathy. Semin Nephrol. 1998;18:622–632.[PubMed][Google Scholar]
  • 32. Nagai N, et al Embryonic lethality of molecular chaperone hsp47 knockout mice is associated with defects in collagen biosynthesis. J Cell Biol. 2000;150:1499–1506.[Google Scholar]
  • 33. Neilson EG, et al. Spontaneous interstitial nephritis in kdkd mice. I. An experimental model of autoimmune renal disease. J Immunol. 1984;133:2560–2565.[PubMed]
  • 34. Kelman ZPCNA: structure, functions and interactions. Oncogene. 1997;14:629–640.[PubMed][Google Scholar]
  • 35. Slack JM, Tosh DTransdifferentiation and metaplasia—switching cell types. Curr Opin Genet Dev. 2001;11:581–586.[PubMed][Google Scholar]
  • 36. Sun D, Baur S, Hay EDEpithelial-mesenchymal transformation is the mechanism for fusion of the craniofacial primordia involved in morphogenesis of the chicken lip. Dev Biol. 2000;228:337–349.[PubMed][Google Scholar]
  • 37. Hay EDAn overview of epithelio-mesenchymal transformation. Acta Anat. 1995;154:8–20.[PubMed][Google Scholar]
  • 38. Owen M, Friedenstein AJStromal stem cells: marrow-derived osteogenic precursors. Ciba Found Symp. 1988;136:42–60.[PubMed][Google Scholar]
  • 39. Garrett DM, Conrad GWFibroblast-like cells from embryonic chick cornea, heart, and skin are antigenically distinct. Dev Biol. 1979;70:50–70.[PubMed][Google Scholar]
  • 40. Schor SL, Schor AMClonal heterogeneity in fibroblast phenotype: implications for the control of epithelial-mesenchymal interactions. Bioessays. 1987;7:200–204.[PubMed][Google Scholar]
  • 41. 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][Google Scholar]
  • 42. Muller GA, Strutz FMRenal fibroblast heterogeneity. Kidney Int Suppl. 1995;50:S33–S36.[PubMed][Google Scholar]
  • 43. Alvarez RJ, et al Biosynthetic and proliferative characteristics of tubulointerstitial fibroblasts probed with paracrine cytokines. Kidney Int. 1992;41:14–23.[PubMed][Google Scholar]
  • 44. Fan JM, et al Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro. Kidney Int. 1999;56:1455–1467.[PubMed][Google Scholar]
  • 45. Desmouliere A, Geinoz A, Gabbiani F, Gabbiani GTransforming growth factor–beta1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol. 1993;122:103–111.[Google Scholar]
  • 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.[Google Scholar]
  • 47. 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][Google Scholar]
  • 48. Rossert J, Eberspaecher H, de Crombrugghe BSeparate cis-acting DNA elements of the mouse pro-alpha 1(I) collagen promoter direct expression of reporter genes to different type I collagen-producing cells in transgenic mice. J Cell Biol. 1995;129:1421–1432.[Google Scholar]
  • 49. 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.[Google Scholar]
  • 50. Jelaska A, Strehlow D, Korn JHFibroblast heterogeneity in physiological conditions and fibrotic disease. Semin Immunopathol. 1999;21:385–395.[PubMed][Google Scholar]
  • 51. Serini G, Gabbiani GMechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res. 1999;250:273–283.[PubMed][Google Scholar]
  • 52. Tang WW, Van GY, Qi MMyofibroblast and alpha 1 (III) collagen expression in experimental tubulointerstitial nephritis. Kidney Int. 1997;51:926–931.[PubMed][Google Scholar]
  • 53. Eyden BThe myofibroblast: an assessment of controversial issues and a definition useful in diagnosis and research. Ultrastruct Pathol. 2001;25:39–50.[PubMed][Google Scholar]
  • 54. Poulsom R, et al Bone marrow contributes to renal parenchymal turnover and regeneration. J Pathol. 2001;195:229–235.[PubMed][Google Scholar]
  • 55. Cornacchia F, et al Glomerulosclerosis is transmitted by bone marrow–derived mesangial cell progenitors. J Clin Invest. 2001;108:1649–1656. doi:10.1172/JCI200112916.[Google Scholar]
  • 56. Barasch J, et al Mesenchymal to epithelial conversion in rat metanephros is induced by LIF. Cell. 1999;99:377–386.[PubMed][Google Scholar]
  • 57. Huss RIsolation of primary and immortalized CD34-hematopoietic and mesenchymal stem cells from various sources. Stem Cells. 2000;18:1–9.[PubMed][Google Scholar]
  • 58. Bi LX, Simmons DJ, Hawkins HK, Cox RA, Mainous EGComparative morphology of the marrow sac. Anat Rec. 2000;260:410–415.[PubMed][Google Scholar]
  • 59. Simmons DJThe in vivo role of bone marrow fibroblast-like stromal cells. Calcif Tissue Int. 1996;58:129–132.[PubMed][Google Scholar]
  • 60. 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][Google Scholar]
  • 61. 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 USA. 1995;92:748–752.[Google Scholar]
  • 62. Huss RPerspectives on the morphology and biology of CD34-negative stem cells. J Hematother Stem Cell Res. 2000;9:783–793.[PubMed][Google Scholar]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.