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Origin and function of myofibroblasts in kidney fibrosis


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Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to-mesenchymal transition program (5%). Specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)+ cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis.

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Figure 1: αSMA+ myofibroblasts derive from resident tissue cells and bone marrow and functionally contribute to renal fibrosis.
Figure 2: Bone marrow–derived myofibroblasts contribute to fibrosis and emerge independently of proliferation.
Figure 3: Bone marrow–derived cells differentiate into αSMA+ myofibroblasts in fibrosis through the Tgfbr2 signaling pathway.
Figure 4: NG2+ and Pdgfrb+ pericytes accumulate in the interstitium but do not functionally contribute to fibrosis.
Figure 5: The EMT contributes to myofibroblasts in fibrosis.

Change history

  • 07 October 2013

     In the version of this article initially published, the original panels intended for publication in Figure 2b were accidentally placed by the authors on top of other panels from a different experiment. As one of the overlapping images was semitransparent, the published imaged was the combination of two different micrographs. The error has been corrected in the HTML and PDF versions of the article.


  1. Gabbiani, G. The myofibroblast in wound healing and fibrocontractive diseases. J. Pathol. 200, 500–503 (2003).

    Article  CAS  Google Scholar 

  2. Sugimoto, H., Mundel, T.M., Kieran, M.W. & Kalluri, R. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol. Ther. 5, 1640–1646 (2006).

    Article  CAS  Google Scholar 

  3. Meran, S. & Steadman, R. Fibroblasts and myofibroblasts in renal fibrosis. Int. J. Exp. Pathol. 92, 158–167 (2011).

    Article  CAS  Google Scholar 

  4. Humphreys, B.D. et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am. J. Pathol. 176, 85–97 (2010).

    Article  CAS  Google Scholar 

  5. 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. 173, 1617–1627 (2008).

    Article  CAS  Google Scholar 

  6. Rønnov-Jessen, L., Petersen, O.W., Koteliansky, V.E. & Bissell, M.J. 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, 859–873 (1995).

    Article  Google Scholar 

  7. Armulik, A., Genove, G. & Betsholtz, C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193–215 (2011).

    Article  CAS  Google Scholar 

  8. Hall, A.P. Review of the pericyte during angiogenesis and its role in cancer and diabetic retinopathy. Toxicol. Pathol. 34, 763–775 (2006).

    Article  CAS  Google Scholar 

  9. Iwano, M. et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110, 341–350 (2002).

    Article  CAS  Google Scholar 

  10. Kalluri, R. & Neilson, E.G. Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Invest. 112, 1776–1784 (2003).

    Article  CAS  Google Scholar 

  11. Zeisberg, M. & Kalluri, R. Fibroblasts emerge via epithelial-mesenchymal transition in chronic kidney fibrosis. Front. Biosci. 13, 6991–6998 (2008).

    Article  CAS  Google Scholar 

  12. Zeisberg, M. & Kalluri, R. The role of epithelial-to-mesenchymal transition in renal fibrosis. J. Mol. Med. 82, 175–181 (2004).

    Article  Google Scholar 

  13. Li, J., Qu, X. & Bertram, J.F. Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice. Am. J. Pathol. 175, 1380–1388 (2009).

    Article  CAS  Google Scholar 

  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. 19, 2282–2287 (2008).

    Article  Google Scholar 

  15. Broekema, M. et al. Bone marrow-derived myofibroblasts contribute to the renal interstitial myofibroblast population and produce procollagen I after ischemia/reperfusion in rats. J. Am. Soc. Nephrol. 18, 165–175 (2007).

    Article  CAS  Google Scholar 

  16. Li, J., Deane, J.A., Campanale, N.V., Bertram, J.F. & Ricardo, S.D. The contribution of bone marrow-derived cells to the development of renal interstitial fibrosis. Stem Cells 25, 697–706 (2007).

    Article  CAS  Google Scholar 

  17. LeBleu, V.S. et al. Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis. Nat. Med. 19, 227–231 (2013).

    Article  CAS  Google Scholar 

  18. LeBleu, V. et al. Stem cell therapies benefit Alport syndrome. J. Am. Soc. Nephrol. 20, 2359–2370 (2009).

    Article  CAS  Google Scholar 

  19. LeBleu, V.S., Sugimoto, H., Miller, C.A., Gattone, V.H. II & Kalluri, R. Lymphocytes are dispensable for glomerulonephritis but required for renal interstitial fibrosis in matrix defect induced Alport renal disease. Lab. Invest. 88, 284–292 (2008).

    Article  CAS  Google Scholar 

  20. Leask, A. & Abraham, D.J. TGF-β signaling and the fibrotic response. FASEB J. 18, 816–827 (2004).

    Article  CAS  Google Scholar 

  21. Chytil, A., Magnuson, M.A., Wright, C.V. & Moses, H.L. Conditional inactivation of the TGF-β type II receptor using Cre:Lox. Genesis 32, 73–75 (2002).

    Article  CAS  Google Scholar 

  22. Ozerdem, U., Grako, K.A., Dahlin-Huppe, K., Monosov, E. & Stallcup, W.B. NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis. Dev. Dyn. 222, 218–227 (2001).

    Article  CAS  Google Scholar 

  23. Bergers, G. & Song, S. The role of pericytes in blood-vessel formation and maintenance. Neuro-oncol. 7, 452–464 (2005).

    Article  CAS  Google Scholar 

  24. Cooke, V.G. et al. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell 21, 66–81 (2012).

    Article  CAS  Google Scholar 

  25. Díaz-Flores, L. et al. Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche. Histol. Histopathol. 24, 909–969 (2009).

    PubMed  Google Scholar 

  26. Hirschi, K.K. & D'Amore, P.A. Pericytes in the microvasculature. Cardiovasc. Res. 32, 687–698 (1996).

    Article  CAS  Google Scholar 

  27. Lindahl, P., Johansson, B.R., Leveen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B–deficient mice. Science 277, 242–245 (1997).

    Article  CAS  Google Scholar 

  28. Song, S., Ewald, A.J., Stallcup, W., Werb, Z. & Bergers, G. PDGFRβ+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat. Cell Biol. 7, 870–879 (2005).

    Article  CAS  Google Scholar 

  29. Foo, S.S. et al. Ephrin-B2 controls cell motility and adhesion during blood-vessel–wall assembly. Cell 124, 161–173 (2006).

    Article  CAS  Google Scholar 

  30. Abraham, S., Kogata, N., Fassler, R. & Adams, R.H. Integrin β1 subunit controls mural cell adhesion, spreading, and blood vessel wall stability. Circ. Res. 102, 562–570 (2008).

    Article  CAS  Google Scholar 

  31. Kriz, W., Kaissling, B. & Le Hir, M. Epithelial-mesenchymal transition (EMT) in kidney fibrosis: fact or fantasy? J. Clin. Invest. 121, 468–474 (2011).

    Article  CAS  Google Scholar 

  32. Liu, Y. New insights into epithelial-mesenchyal transition in kidney fibrosis. J. Am. Soc. Nephrol. 21, 212–222 (2010).

    Article  CAS  Google Scholar 

  33. Sugimoto, H. et al. Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis. Nat. Med. 18, 396–404 (2012).

    Article  CAS  Google Scholar 

  34. Collett, G.D. & Canfield, A.E. Angiogenesis and pericytes in the initiation of ectopic calcification. Circ. Res. 96, 930–938 (2005).

    Article  CAS  Google Scholar 

  35. Hashimoto, N. et al. Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 43, 161–172 (2010).

    Article  CAS  Google Scholar 

  36. Zeisberg, E.M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med. 13, 952–961 (2007).

    Article  CAS  Google Scholar 

  37. Rock, J.R. et al. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc. Natl. Acad. Sci. USA 108, E1475–E1483 (2011).

    Article  CAS  Google Scholar 

  38. Zeisberg, M. et al. BMP-7 counteracts TGF-β1–induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med. 9, 964–968 (2003).

    Article  CAS  Google Scholar 

  39. Tondreau, T. et al. Isolation of BM mesenchymal stem cells by plastic adhesion or negative selection: phenotype, proliferation kinetics and differentiation potential. Cytotherapy 6, 372–379 (2004).

    Article  CAS  Google Scholar 

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This study was supported by US National Institutes of Health (NIH) grants DK55001, DK81976, CA125550, CA155370, CA163191 and CA151925 (all to R.K.). R.K. is supported by the Cancer Prevention and Research Institute of Texas and the Metastasis Research Center at MD Anderson Cancer Center. V.S.L. was funded by the NIH Research Training Grant in Gastroenterology (2T32DK007760-11), V.G.C. was funded by the US National Research Service Award (NRSA) F32 Ruth Kirschstein Post-doctoral Fellowship from the NIH (5F32DK082119-02). H.S. was funded by the NIH Research Training Grant in Cardiovascular Biology (5T32HL007374-30). J.O. was funded by the US Department of Defense Breast Cancer Research Predoctoral Traineeship Award (W81XWH-09-1-0008). G.T. was funded by the International Society of Nephrology Fellowship. C.W. was funded by the NIH Research Training Grant in Pediatric Nephrology (T32DK007726). Pdgfrb-Cre mice were kindly provided by R. Adams, Max Planck Institute for Molecular Biomedicine. γGT-Cre mice were kindly provided by E. Neilson, Northwestern University. Tgfbr2flox/flox mice were kindly provided by H. Moses, Vanderbilt University.

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Authors and Affiliations



R.K. provided the conceptual framework and intellectual input, designed the study and helped in the writing of the manuscript. V.S.L. designed the study, provided intellectual input, performed experiments, collected data and wrote the manuscript. V.S.L., G.T., Y.T., V.G.C., H.S., J.O. and C.W. performed some experiments and collected data. The data was analyzed by V.S.L., G.T., H.S. and C.W.

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Correspondence to Raghu Kalluri.

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The authors declare no competing financial interests.

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LeBleu, V., Taduri, G., O'Connell, J. et al. Origin and function of myofibroblasts in kidney fibrosis. Nat Med 19, 1047–1053 (2013).

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