Pediatric Nephrology

, Volume 27, Issue 2, pp 183–193 | Cite as

The origin of interstitial myofibroblasts in chronic kidney disease

  • Ivica Grgic
  • Jeremy S. Duffield
  • Benjamin D. Humphreys
Review

Abstract

Chronic kidney diseases (CKD), independent of their primary cause, lead to progressive, irreversible loss of functional renal parenchyma. Renal pathology in CKD is characterized by tubulointerstitial fibrosis with excessive matrix deposition produced by myofibroblasts. Because blocking the formation of these scar-forming cells represents a logical therapeutic target for patients with progressive fibrotic kidney disease, the origin of renal myofibroblasts is a subject of intense investigation. Although the traditional view holds that resident fibroblasts are the myofibroblast precursor, for the last 10 years, injured epithelial cells have been thought to directly contribute to the myofibroblast pool by the process of epithelial-to-mesenchymal transition (EMT). The recent application of genetic fate mapping techniques in mouse fibrosis models has provided new insights into the cell hierarchies in fibrotic kidney disease and results cast doubt on the concept that EMT is a source of myofibroblast recruitment in vivo, but rather point to the resident pericyte/perivascular fibroblast as the myofibroblast progenitor pool. This review will highlight recent findings arguing against EMT as a direct contributor to the kidney myofibroblast population and review the use of genetic fate mapping to elucidate the cellular mechanisms of kidney homeostasis and disease.

Keywords

Fibrosis EMT Myofibroblast Chronic kidney disease Genetic fate mapping 

References

  1. 1.
    Wynn TA (2007) Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 117:524–529PubMedCrossRefGoogle Scholar
  2. 2.
    Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214:199–210PubMedCrossRefGoogle Scholar
  3. 3.
    Bohle A, Strutz F, Muller GA (1994) On the pathogenesis of chronic renal failure in primary glomerulopathies: a view from the interstitium. Exp Nephrol 2:205–210PubMedGoogle Scholar
  4. 4.
    Nankivell BJ, Fenton-Lee CA, Kuypers DR, Cheung E, Allen RD, O'Connell PJ, Chapman JR (2001) Effect of histological damage on long-term kidney transplant outcome. Transplantation 71:515–523PubMedCrossRefGoogle Scholar
  5. 5.
    Qi W, Chen X, Poronnik P, Pollock CA (2006) The renal cortical fibroblast in renal tubulointerstitial fibrosis. Int J Biochem Cell Biol 38:1–5PubMedCrossRefGoogle Scholar
  6. 6.
    Skalli O, Ropraz P, Trzeciak A, Benzonana G, Gillessen D, Gabbiani G (1986) A monoclonal antibody against alpha-smooth muscle actin: a new probe for smooth muscle differentiation. J Cell Biol 103:2787–2796PubMedCrossRefGoogle Scholar
  7. 7.
    Serini G, Gabbiani G (1999) Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res 250:273–283PubMedCrossRefGoogle Scholar
  8. 8.
    Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3:349–363PubMedCrossRefGoogle Scholar
  9. 9.
    Darby I, Skalli O, Gabbiani G (1990) Alpha-smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing. Lab Invest 63:21–29PubMedGoogle Scholar
  10. 10.
    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 122:103–111PubMedCrossRefGoogle Scholar
  11. 11.
    Serini G, Bochaton-Piallat ML, Ropraz P, Geinoz A, Borsi L, Zardi L, Gabbiani G (1998) The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1. J Cell Biol 142:873–881PubMedCrossRefGoogle Scholar
  12. 12.
    Bechtel W, McGoohan S, Zeisberg EM, Muller GA, Kalbacher H, Salant DJ, Muller CA, Kalluri R, Zeisberg M (2010) Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med 16:544–550PubMedCrossRefGoogle Scholar
  13. 13.
    Cohnheim J (1867) Ueber Entzuendung und Eiterung. Virchows Arch 40:1–79CrossRefGoogle Scholar
  14. 14.
    Ross R, Everett NB, Tyler R (1970) Wound healing and collagen formation. VI. The origin of the wound fibroblast studied in parabiosis. J Cell Biol 44:645–654PubMedCrossRefGoogle Scholar
  15. 15.
    Kalluri R, Neilson EG (2003) Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 112:1776–1784PubMedGoogle Scholar
  16. 16.
    Liu Y (2010) New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol 21:212–222PubMedCrossRefGoogle Scholar
  17. 17.
    Greenburg G, Hay ED (1982) Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol 95:333–339PubMedCrossRefGoogle Scholar
  18. 18.
    Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890PubMedCrossRefGoogle Scholar
  19. 19.
    Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14:818–829PubMedCrossRefGoogle Scholar
  20. 20.
    Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428PubMedCrossRefGoogle Scholar
  21. 21.
    Liu Y (2004) Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol 15:1–12PubMedCrossRefGoogle Scholar
  22. 22.
    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 110:341–350PubMedGoogle Scholar
  23. 23.
    Witzgall R, Brown D, Schwarz C, Bonventre JV (1994) Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a heterogenous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells. J Clin Invest 93:2175–2188PubMedCrossRefGoogle Scholar
  24. 24.
    Grone HJ, Weber K, Grone E, Helmchen U, Osborn M (1987) Coexpression of keratin and vimentin in damaged and regenerating tubular epithelia of the kidney. Am J Pathol 129:1–8PubMedGoogle Scholar
  25. 25.
    Le Hir M, Hegyi I, Cueni-Loffing D, Loffing J, Kaissling B (2005) Characterization of renal interstitial fibroblast-specific protein 1/S100A4-positive cells in healthy and inflamed rodent kidneys. Histochem Cell Biol 123:335–346PubMedCrossRefGoogle Scholar
  26. 26.
    Lin SL, Kisseleva T, Brenner DA, Duffield JS (2008) Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am J Pathol 173:1617–1627PubMedCrossRefGoogle Scholar
  27. 27.
    Li L, Zepeda-Orozco D, Black R, Lin F (2010) Autophagy is a component of epithelial cell fate in obstructive uropathy. Am J Pathol 176:1767–1778PubMedCrossRefGoogle Scholar
  28. 28.
    Joyner AL, Zervas M (2006) Genetic inducible fate mapping in mouse: establishing genetic lineages and defining genetic neuroanatomy in the nervous system. Dev Dyn 235:2376–2385PubMedCrossRefGoogle Scholar
  29. 29.
    Duffield JS, Humphreys BD (2010) Origin of new cells in the adult kidney: results from genetic labeling techniques. Kidney Int. doi:10.1038/ki.2010.338 PubMedGoogle Scholar
  30. 30.
    Hayashi S, McMahon AP (2002) Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev Biol 244:305–318PubMedCrossRefGoogle Scholar
  31. 31.
    Humphreys BD, Valerius MT, Kobayashi A, Mugford JW, Soeung S, Duffield JS, McMahon AP, Bonventre JV (2008) Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell 2:284–291PubMedCrossRefGoogle Scholar
  32. 32.
    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 176:85–97PubMedCrossRefGoogle Scholar
  33. 33.
    Endo T, Okuda T, Nakamura J, Higashi AY, Fukatsu A, Kita T, Yanagita M (2010) Exploring the origin of the cells responsible for regeneration and fibrosis in the kidneys. J Am Soc Nephrol (Abstract) 21:F-FC163.Google Scholar
  34. 34.
    Koesters R, Kaissling B, Lehir M, Picard N, Theilig F, Gebhardt R, Glick AB, Hahnel B, Hosser H, Grone HJ, Kriz W (2010) Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells. Am J Pathol 177:632–643PubMedCrossRefGoogle Scholar
  35. 35.
    Zeisberg M, Bottiglio C, Kumar N, Maeshima Y, Strutz F, Muller GA, Kalluri R (2003) Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am J Physiol Renal Physiol 285:F1060–1067PubMedGoogle Scholar
  36. 36.
    Bielesz B, Sirin Y, Si H, Niranjan T, Gruenwald A, Ahn S, Kato H, Pullman J, Gessler M, Haase VH, Susztak K (2010) Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans. J Clin Invest 120:4040–4054PubMedCrossRefGoogle Scholar
  37. 37.
    Taura K, Miura K, Iwaisako K, Osterreicher CH, Kodama Y, Penz-Osterreicher M, Brenner DA (2010) Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice. Hepatology 51:1027–1036PubMedCrossRefGoogle Scholar
  38. 38.
    Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410:701–705PubMedCrossRefGoogle Scholar
  39. 39.
    Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, Pasumarthi KB, Virag JI, Bartelmez SH, Poppa V, Bradford G, Dowell JD, Williams DA, Field LJ (2004) Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428:664–668PubMedCrossRefGoogle Scholar
  40. 40.
    Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC (2004) Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 428:668–673PubMedCrossRefGoogle Scholar
  41. 41.
    Zeisberg M, Duffield JS (2010) Resolved: EMT produces fibroblasts in the kidney. J Am Soc Nephrol 21:1247–1253PubMedCrossRefGoogle Scholar
  42. 42.
    Cook HT (2010) The origin of renal fibroblasts and progression of kidney disease. Am J Pathol 176:22–24PubMedCrossRefGoogle Scholar
  43. 43.
    Wiggins R, Goyal M, Merritt S, Killen PD (1993) Vascular adventitial cell expression of collagen I messenger ribonucleic acid in anti-glomerular basement membrane antibody-induced crescentic nephritis in the rabbit. A cellular source for interstitial collagen synthesis in inflammatory renal disease. Lab Invest 68:557–565PubMedGoogle Scholar
  44. 44.
    Faulkner JL, Szcykalski LM, Springer F, Barnes JL (2005) Origin of interstitial fibroblasts in an accelerated model of angiotensin II-induced renal fibrosis. Am J Pathol 167:1193–1205PubMedCrossRefGoogle Scholar
  45. 45.
    Picard N, Baum O, Vogetseder A, Kaissling B, Le Hir M (2008) Origin of renal myofibroblasts in the model of unilateral ureter obstruction in the rat. Histochem Cell Biol 130:141–155PubMedCrossRefGoogle Scholar
  46. 46.
    Grone HJ, Kriz W (2010) Cells involved in renal tubulointerstitial degeneration and fibrosis—A matter of differentiation or cell lineage switch? ISN nexus Fibrosis and the Kidney. International Society of Nephrology, Geneva, Switzerland.Google Scholar
  47. 47.
    Scholten D, Osterreicher CH, Scholten A, Iwaisako K, Gu G, Brenner DA, Kisseleva T (2010) Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice. Gastroenterology 139:987–998PubMedCrossRefGoogle Scholar
  48. 48.
    Duffield JS (2010) Epithelial to mesenchymal transition in injury of solid organs: fact or artifact? Gastroenterology 139(4):1081–1083PubMedCrossRefGoogle Scholar
  49. 49.
    Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, Kalluri R (2007) Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 282:23337–23347PubMedCrossRefGoogle Scholar
  50. 50.
    Wells RG (2010) The epithelial-to-mesenchymal transition in liver fibrosis: here today, gone tomorrow? Hepatology 51:737–740PubMedGoogle Scholar
  51. 51.
    Wada T, Sakai N, Matsushima K, Kaneko S (2007) Fibrocytes: a new insight into kidney fibrosis. Kidney Int 72:269–273PubMedCrossRefGoogle Scholar
  52. 52.
    Roufosse C, Bou-Gharios G, Prodromidi E, Alexakis C, Jeffery R, Khan S, Otto WR, Alter J, Poulsom R, Cook HT (2006) Bone marrow-derived cells do not contribute significantly to collagen I synthesis in a murine model of renal fibrosis. J Am Soc Nephrol 17:775–782PubMedCrossRefGoogle Scholar
  53. 53.
    Zeisberg EM, Potenta SE, Sugimoto H, Zeisberg M, Kalluri R (2008) Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J Am Soc Nephrol 19:2282–2287PubMedCrossRefGoogle Scholar
  54. 54.
    Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB, Neilson EG, Sayegh MH, Izumo S, Kalluri R (2007) Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 13:952–961PubMedCrossRefGoogle Scholar
  55. 55.
    Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G (2007) The myofibroblast: one function, multiple origins. Am J Pathol 170:1807–1816PubMedCrossRefGoogle Scholar
  56. 56.
    Levinson RS, Batourina E, Choi C, Vorontchikhina M, Kitajewski J, Mendelsohn CL (2005) Foxd1-dependent signals control cellularity in the renal capsule, a structure required for normal renal development. Development 132:529–539PubMedCrossRefGoogle Scholar
  57. 57.
    Hatini V, Huh SO, Herzlinger D, Soares VC, Lai E (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev 10:1467–1478PubMedCrossRefGoogle Scholar
  58. 58.
    Rouget C (1873) Memoire sur le developpement, la structure et les proprietes physiologiques des capillaires sanguins et lymphatiques. Arch Physiol Norm et Path 5:603–663Google Scholar
  59. 59.
    Courtnoy P, Boyles J (1983) Fibronectin in the microvasculature: localization in the pericyte-endothelial interstitium. J Ultrastruct Res 83:258–273CrossRefGoogle Scholar
  60. 60.
    Kaissling B, Hegyi I, Loffing J, Le Hir M (1996) Morphology of interstitial cells in the healthy kidney. Anat Embryol (Berl) 193:303–318CrossRefGoogle Scholar
  61. 61.
    Diaz-Flores L, Gutierrez R, Madrid JF, Varela H, Valladares F, Acosta E, Martin-Vasallo P, Diaz-Flores L Jr (2009) Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche. Histol Histopathol 24:909–969PubMedGoogle Scholar
  62. 62.
    Nehls V, Drenckhahn D (1991) Heterogeneity of microvascular pericytes for smooth muscle type alpha-actin. J Cell Biol 113:147–154PubMedCrossRefGoogle Scholar
  63. 63.
    Ronnov-Jessen L, Petersen OW, Koteliansky VE, Bissell MJ (1995) The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest 95:859–873PubMedCrossRefGoogle Scholar
  64. 64.
    Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Peault B (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3:301–313PubMedCrossRefGoogle Scholar
  65. 65.
    Lin S, Chang F, Schrimpf C, Chen Y, Wu C, Wu V, Chiang W, Kuhnert F, Kuo CJ, Chen Y, Wu K, Tsai T, Duffield JS (2011) Targeting endothelium-pericyte cross talk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis. Am J Pathol 178:911–923PubMedCrossRefGoogle Scholar
  66. 66.
    Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV (2010) Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med 16:535–543, 531p following 143PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2011

Authors and Affiliations

  • Ivica Grgic
    • 1
    • 2
  • Jeremy S. Duffield
    • 3
  • Benjamin D. Humphreys
    • 1
    • 4
  1. 1.Renal DivisionBrigham and Women’s HospitalBostonUSA
  2. 2.Department of Internal Medicine and NephrologyPhilipps-UniversityMarburgGermany
  3. 3.Division of Nephrology & Institute for Stem Cell and Regenerative Medicine, Laboratory of Inflammation ResearchUniversity of WashingtonSeattleUSA
  4. 4.Harvard Stem Cell InstituteCambridgeUSA

Personalised recommendations