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Endothelial-to-mesenchymal transition contributes to cardiac fibrosis

Nature Medicine volume 13, pages 952–961 (2007)Cite this article

Abstract

Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-β1 (TGF-β1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.

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Figure 1: Lineage tracing of EndMT in Tie1Cre;R26RstoplacZ mice.
Figure 2: Bone marrow–derived Tie1+ cells in cardiac fibrosis.
Figure 3: EndMT in cardiac fibrosis is mediated by TGF-β1 in a Smad-dependent manner.
Figure 4: rhBMP-7 inhibits TGF-β1–induced EndMT in HCEC.
Figure 5: Inhibition of cardiac fibrosis induced by aortic banding by rhBMP-7 is associated with inhibition of EndMT.
Figure 6: Treatment with rhBMP-7 inhibits cardiac fibrosis and reduces EndMT in a model of chronic rejection.

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Acknowledgements

This study was partially funded by research grants DK62987, AA13913, DK61688 and DK55001 from the NIH, partially by a research grant from Novartis Corporation, and partly by a research fund from the Beth Israel Deaconess Medical Center for the Division of Matrix Biology. E.Z. was funded by a fellowship grant from the Leopoldina Academy (BMBF-LPD 9901/8-105) and is currently funded by a Ruth L. Kirschstein National Research Service Award from the NIH (5 F32 HL082436-01). M.Z. is funded by NIH grant 5K08DK074558-01 and the ASN Carl W. Gottschalk Award. EGN is funded by a NIH grant (DK-46282). Parts of this study were presented as an oral presentation at the American Heart Association 2004. We thank V. Toxavidis and J. Tigges from the Beth Israel Deaconess Medical Center Flow Cytometry and Cell Sorting Core Facility for their help with the FACS sorting as well as S. McGoohan for technical assistance with the real-time PCR.

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Authors and Affiliations

  1. Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, 02215, Massachusetts, USA

    Elisabeth M Zeisberg, Michael Zeisberg & Raghu Kalluri

  2. Novartis Institute for Biomedical Research, Cambridge, 02139, Massachusetts, USA

    Oleg Tarnavski & Seigo Izumo

  3. Department of Cardiology, Children's Hospital, Boston, 02115, Massachusetts, USA

    Adam L Dorfman & William T Pu

  4. Cardiovascular Division, Department of Medicine, Department of Cardiology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, 02215, Massachusetts, USA

    Julie R McMullen

  5. Department of Experimental Pathology, Lund University, Lund, 22185, Sweden

    Erika Gustafsson

  6. Transplantation Research Center, Brigham and Women's Hospital & Children's Hospital, Boston, 02215, Massachusetts, USA

    Anil Chandraker, Xueli Yuan & Mohamed H Sayegh

  7. Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Anita B Roberts

  8. Department of Medicine, Vanderbilt University, Nashville, 37215, Tennessee, USA

    Eric G Neilson

  9. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Raghu Kalluri

  10. Harvard-MIT Division of Health Sciences and Technology, Boston, 02215, Massachusetts, USA

    Raghu Kalluri

Authors
  1. Elisabeth M Zeisberg
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Contributions

E.M.Z.: tissue analysis, immuno-labeling, FISH, EndMT cell culture experiments, bone marrow transplantation, animal husbandry, design of experiments, data analysis and interpretation, substantial contribution to manuscript preparation, writing and generation of all figures. O.T.: All aortic banding surgeries and invasive hemodynamic measurements. M.Z.: isolation of primary heart fibroblasts, MTT assay, collagen ELISA, contribution to conceptual design, data analysis, data discussion and manuscript editing. A.L.D.: echocardiography of mice. J.R.M.: data discussion and manuscript editing. E.G.: generation of Tie1Cre mice. A.C.: study design of transplantation experiments. X.Y.: transplantation surgeries. W.T.P.: AV cushion isolation. A.B.R.: generation of Smad3+/− mice. E.G.N.: manuscript editing, data discussion, generation of FSP1-GFP mice. M.H.S.: study design of transplantation experiments. S.I.: contribution to conceptual design of aortic banding experiments, manuscript editing, data discussion. R.K.: principal investigator of the study; overall study design to address the conceptual ideas; analysis and interpretation of the data, drafting and final editing of the manuscript.

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Correspondence to Raghu Kalluri.

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Zeisberg, E., Tarnavski, O., Zeisberg, M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 13, 952–961 (2007). https://doi.org/10.1038/nm1613

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