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NDT Advance Access originally published online on August 3, 2006
Nephrology Dialysis Transplantation 2006 21(12):3368-3370; doi:10.1093/ndt/gfl199
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Renal fibrosis and the origin of the renal fibroblast

Frank Strutz and Gerhard A. Müller

Department of Nephrology and Rheumatology, Georg-August-University Medical Center, Göttingen, Germany

Correspondence and offprint requests to: Frank Strutz, MD, Department of Nephrology and Rheumatology, Georg-August-University Medical Center, Robert-Koch-Str. 40, 37099 Goettingen. Email: fstrutz{at}gwdg.de

Keywords: cortical fibroblast; epithelial mesenchymal transition; fibrosis; progression

Many studies have determined that the extent of tubulointerstitial involvement, particularly fibrosis, correlates better with renal function than glomerular changes do, thus, the extent of tubulointerstitial damage in any given renal biopsy has important implications for the renal prognosis of the patient (summarized in [1]). Tubulointerstitial fibrosis is characterized by the accumulation of extracellular matrix components including collagen types I, III, IV, proteoglycans and fibronectin. In recent years, much controversy has been created in the nephrology community regarding the origin of matrix-producing cells in the kidney. Several possibilities exist, including activation of resident interstitial fibroblasts, migrating haematopoietic or mesenchymal stem cells from the bone marrow, periadventitial cells and epithelial–mesenchymal transition (EMT) of tubular epithelial cells. This review summarizes recent data indicating the possible origin of matrix-producing cells in the kidney, and illustrates from a clinical point of view why this may be important.

Traditionally, resident interstitial fibroblasts have been thought to be the sole source of extracellular matrix. In 1867, Cohnheim published a classical article on mechanisms of inflammation, stating that fibroblasts (called contractile cellular elements at that time) are descendents of migrating leucocytes [2]. This theory was widely believed for over a century, until Ross and coworkers [3] demonstrated, in a very elegant set of experiments with the use of parabiotic rats, that fibroblasts were of local origin. Nevertheless, recent studies point again to a possible bone marrow origin of at least some fibroblasts and the concept of fibroblast stem cells has gained wide popularity, though its exact contribution remains to be determined [4]. Moreover, periadventitial cells [5] and tubular epithelial cells [6] have been implicated as the origin of matrix-producing cells. Figure 1 summarizes the possible origins of cells synthesizing extracellular matrix within the tubulointerstitium.


Figure 1
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  		Fig. 1. Possible origins of extracellular matrix-producing cells in the kidney.

 


   Myofibroblasts and non-myofibroblasts
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 Myofibroblasts and non...
Is the origin of...
 Therapeutic implications
 Conclusion
 References
 
Fibroblasts are thought to convert to the so-called myofibroblasts (due to the de novo expression of {alpha}-smooth muscle actin whose expression is normally confined to vascular smooth muscle cells) during fibrogenesis. Several markers have been advocated for the labelling of renal cortical fibroblasts including nerve growth factor, platelet-derived growth factor-{alpha} and-ß receptors, CD90, exto-5'-nucleotidase and fibroblast-specific protein-1 (FSP-1) [7]. Identifying these cells remains challenging however, and they are often identified by their cell shape as a prototypical mesenchmyal cell. The de novo expression of {alpha}-smooth muscle actin is not the only change during the transition from fibroblast to myofibroblast, indicating that this population may be more heterogeneous than commonly appreciated. Moreover, the radical change in phenotype is often underappreciated [8] and makes tracking of these cells difficult. The differences between fibroblasts from normal and fibrotic kidneys extend to their proliferative activity and matrix synthesis capacity [9].

As outlined above, activated resident interstitial fibroblasts are not the only cells participating in extracellular matrix production. A number of studies have confirmed the existence of bone marrow-derived cells within the interstitium [10] and the EMT of bone marrow cells to tubular epithelium [11]. Preliminary evidence using genetically tagged fibroblast and tubular epithelial cells indicates that fibroblasts derived from bone marrow comprise about 12% of the resident interstitial population in normal murine kidneys [12]. In that study, this percentage did not change when an experimental model of progressive renal disease [the rapidly progressive model of unilateral ureteral obstruction (UUO)] was induced. Conversely, up to 36% of the additional extracellular matrix-producing cells are derived from tubular epithelial cells by EMT in that model. EMT is a variant of transdifferentiation and a well-recognized mechanism for dispersing cells in vertebrate embryos [13] and forming fibroblasts in injured tissues [14]. EMT is a dynamic process which involves the gradual loss of epithelial cell markers paired with a gain of mesenchymal markers and has been described mainly in models of rapidly progressive chronic failure. Disruption of the integrity of the tubular basement membrane is a prerequisite for EMT to occur and the composition of the extracellular matrix is known to influence the differentiation state of tubular epithelial cells [15]. Very recently, Yamashita and colleagues [16] determined that renal progenitor tubular cells may undergo EMT and suggested these cells as typical source of interstitial myofibroblasts.



   Is the origin of the renal fibroblast comparable in different forms of progressive renal disease?
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 Myofibroblasts and non...
 Is the origin of...
Therapeutic implications
 Conclusion
 References
 
Recently, Faulkner and colleagues [17] analysed the origin of {alpha}-smooth muscle actin positive cells in an accelerated model of angiotensin II-induced renal fibrosis after habu venom injury. The combination of angiotensin II and habu venom injections induce an accelerated model of renal fibrosis and glomerulosclerosis after 14 days. Using that model, the authors determined that most, if not all, of the tubulointerstitial {alpha}-smooth muscle actin expressing cells were of local origin. No disruption of tubular basement integrity could be detected and no traffic of proximal tubular epithelial cells into the interstitial compartment was seen by labelling with Texan Red dextran [17]. Interestingly, early expansion of {alpha}-smooth actin positive myofibroblasts was seen in perivascular regions, corroborating similar observations by Wiggins et al. [5] in an anti-glomerular basement membrane antibody-induced nephritis and in periglomerular areas, in a study by the same group [18]. Does this mean that activation of resident interstitial fibroblasts is the sole source of myofibroblasts in the angiotensin II/Habu venom model? No, it does not. Firstly, as the authors themselves admit, EMT may still occur, since they focused on the exclusion of proximal tubular epithelial cells as the source of EMT. However, EMT may also occur in distal tubular cells. Secondly, infiltration of marrow-derived haematopoietic or mesenchymal stem cells was not excluded in the study and remains a possibility. Thirdly, as indicated before, using {alpha}-smooth muscle actin expression alone as a marker for matrix-producing cells may not sample all these cells, as was well shown by Okada et al. [19] in a model of murine polycystic kidney disease. Finally, and perhaps most importantly, the origin of matrix-producing cells may vary according to the model used.



   Therapeutic implications
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 Myofibroblasts and non...
 Is the origin of...
 Therapeutic implications
Conclusion
 References
 
Are these findings of relevance for the clinician? Not as yet, but they may prove to be of clinical importance very soon with the advent of novel anti-fibrotic therapeutics. The origin of matrix-producing cells may vary according to the underlying disease and/or the time course of renal fibrogenesis. The predominant origin of matrix-producing cells may have therapeutic implications. For example, despite their anatomic location, interstitial fibroblasts may be excellent targets for gene transfer [20]. On the other hand, the proliferation and stimulation of resident fibroblasts may be less important in other forms of chronic progressive renal disease, such as the experimental UUO model. In that model, as well as the model of nephrotoxic serum nephritis, the formation of activated fibroblasts via EMT may be more important. Blocking EMT by bone morphogenetic protein (BMP)-7 or hepatocyte growth factor inhibit progression and, in the case of BMP-7, may even revert matrix deposition in these models [21]. Conversely, BMP-7 as an anti-fibrotic agent may not work in models where there is no or little EMT, such as the overload proteinuria model [22]. Unfortunately, the relative contribution of cellular sources to the formation of activated fibroblasts in human studies is an area of research that has just begun. Thus, it will be very interesting to see how this information gathered from experimental models will be transferred to clinical studies.



   Conclusion
Top
 Myofibroblasts and non...
 Is the origin of...
 Therapeutic implications
 Conclusion
References
 
The renal fibroblast remains a (partial) mystery. The lack of clear-cut markers to describe this cell has hampered in vivo research of these cells. At the same time, this lack of markers may indicate the heterogeneity of this cell type. Even the myofibroblast, which is easily defined and detected in vivo due to the expression of {alpha}-smooth muscle actin, is probably only one of the several activation states of fibroblasts in the sense of matrix-producing cells. These cells may be derived from resident interstitial cells, mesenchymal and/or haematopoietic stem cells, periadventitial cells and by the process of EMT. The relative contribution of these cellular elements may vary according to the model of progressive renal disease applied. Even more interestingly, this contribution may have therapeutic implications. However, at the same time it must be stressed that almost all of these data have been generated in animal models and their significance for human renal fibrogenesis remains to be determined.

Conflict of interest statement. None declared.



   References
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 Myofibroblasts and non...
 Is the origin of...
 Therapeutic implications
 Conclusion
 References
 

  1. Bohle A, Strutz F, Müller GA. (1994) On the pathogenesis of chronic renal failure in primary glomerulopathies. Exp Nephrol 2:205–210.[Medline]
  2. Cohnheim J. (1867) Über Entzündung und Eiterung. Virchows Arch 40:1–79.
  3. 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 44:645–654.[Abstract/Free Full Text]
  4. Powell DW, Mifflin RC, Valentich JD, et al. (1999) Myofibroblasts. II. Intestinal subepithelial myofibroblasts. Am J Physiol 277:C183–C201.[Web of Science][Medline]
  5. 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. Lab Invest 68:557–565.[Web of Science][Medline]
  6. Strutz F, Okada H, Lo CW, et al. (1995) Identification and characterization of fibroblast-specific protein 1 (FSP1). J Cell Biol 130:393–405.[Abstract/Free Full Text]
  7. Qi W, Chen X, Poronnik P, Pollock CA. (2006) The renal cortical fibroblast in renal tubulointerstitial fibrosis. Int J Biochem Cell Biol 38:1–5.[CrossRef][Web of Science][Medline]
  8. Grinnell F. (1994) Fibroblasts, myofibroblasts, and wound contraction. J Cell Biol 124:401–404.[Free Full Text]
  9. Strutz F, Zeisberg M, Hemmerlein B, et al. (2000) Basic fibroblast growth factor (FGF-2) expression is increased in human renal fibrogenesis and may mediate autocrine fibroblast proliferation. Kidney Int 57:1521–1538.[CrossRef][Web of Science][Medline]
  10. Grimm PC, Nickerson P, Jeffery J, et al. (2001) Neointimal and tubulointerstitial infiltration by recipient mesenchymal cells in chronic renal-allograft rejection. N Engl J Med 345:93–97.[Abstract/Free Full Text]
  11. Poulsom R, Forbes SJ, Hodivala-Dilke K, et al. (2001) Bone marrow contributes to renal parenchymal turnover and regeneration. J Pathol 195:229–235.[CrossRef][Web of Science][Medline]
  12. Iwano M, Plieth D, Danoff TM, et al. (2002) Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 110:341–350.[CrossRef][Web of Science][Medline]
  13. Hay ED and Zuk A. (1995) Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. Am J Kidney Dis 26:678–690.[Web of Science][Medline]
  14. Strutz F and Neilson EG. (2003) New insights into mechanisms of fibrosis in immune renal injury. Springer Semin Immunopathol 24:459–476.[CrossRef][Web of Science][Medline]
  15. Zeisberg M, Maeshima Y, Mosterman B, Kalluri R. (2002) Renal fibrosis. Extracellular matrix microenvironment regulates migratory behavior of activated tubular epithelial cells. Am J Pathol 160:2001–2008.[Abstract/Free Full Text]
  16. Yamashita S, Maeshima A, Nojima Y. (2005) Involvement of renal progenitor tubular cells in epithelial-to-mesenchymal transition in fibrotic rat kidneys. J Am Soc Nephrol 16:2044–2051.[Abstract/Free Full Text]
  17. 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 167:1193–1205.[Abstract/Free Full Text]
  18. Barnes VL, Musa J, Mitchell RJ, Barnes JL. (1999) Expression of embryonic fibronectin isoform EIIIA parallels alpha-smooth muscle actin in maturing and diseased kidney. J Histochem Cytochem 47:787–798.[Abstract/Free Full Text]
  19. Okada H, Ban S, Nagao S, et al. (2000) Progressive renal fibrosis in murine polycystic kidney disease: an immunohistochemical observation. Kidney Int 58:587–597.[CrossRef][Web of Science][Medline]
  20. Sandovici M, Deelman LE, Smit-van Oosten A, et al. (2006) Enhanced transduction of fibroblasts in transplanted kidney with an adenovirus having an RGD motif in the HI loop. Kidney Int 69:45–52.[CrossRef][Web of Science][Medline]
  21. Zeisberg M, Hanai J, Sugimoto H, et al. (2003) BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9:964–968.[CrossRef][Web of Science][Medline]
  22. Ikeda Y, Jung YO, Kim H, et al. (2004) Exogenous bone morphogenetic protein-7 fails to attenuate renal fibrosis in rats with overload proteinuria. Nephron Exp Nephrol 97:123–135.
Received for publication: 29.12.05
Accepted in revised form: 21. 3.06


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