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Origin and function of myofibroblasts in kidney fibrosis

Nature Medicine volume 19, pages 1047–1053 (2013)Cite this article

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Abstract

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.

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Acknowledgements

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

  1. Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Valerie S LeBleu, Hikaru Sugimoto & Raghu Kalluri

  2. Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

    Valerie S LeBleu, Gangadhar Taduri, Joyce O'Connell, Yingqi Teng, Vesselina G Cooke, Craig Woda, Hikaru Sugimoto & Raghu Kalluri

  3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    Raghu Kalluri

  4. Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, Massachusetts, USA

    Raghu Kalluri

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  1. Valerie S LeBleu
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Contributions

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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LeBleu, V., Taduri, G., O'Connell, J. et al. Origin and function of myofibroblasts in kidney fibrosis. Nat Med 19, 1047–1053 (2013). https://doi.org/10.1038/nm.3218

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