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Conversion of vascular endothelial cells into multipotent stem-like cells

Nature Medicine volume 16, pages 1400–1406 (2010)Cite this article

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A Corrigendum to this article was published on 07 April 2011

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Abstract

Mesenchymal stem cells can give rise to several cell types, but varying results depending on isolation methods and tissue source have led to controversies about their usefulness in clinical medicine. Here we show that vascular endothelial cells can transform into multipotent stem-like cells by an activin-like kinase-2 (ALK2) receptor–dependent mechanism. In lesions from individuals with fibrodysplasia ossificans progressiva (FOP), a disease in which heterotopic ossification occurs as a result of activating ALK2 mutations, or from transgenic mice expressing constitutively active ALK2, chondrocytes and osteoblasts expressed endothelial markers. Lineage tracing of heterotopic ossification in mice using a Tie2-Cre construct also suggested an endothelial origin of these cell types. Expression of constitutively active ALK2 in endothelial cells caused endothelial-to-mesenchymal transition and acquisition of a stem cell–like phenotype. Similar results were obtained by treatment of untransfected endothelial cells with the ligands transforming growth factor-β2 (TGF-β2) or bone morphogenetic protein-4 (BMP4) in an ALK2-dependent manner. These stem-like cells could be triggered to differentiate into osteoblasts, chondrocytes or adipocytes. We suggest that conversion of endothelial cells to stem-like cells may provide a new approach to tissue engineering.

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Figure 1: Endothelial cell differentiation in heterotopic ossification.
Figure 2: Constitutively active ALK2 promotes EndMT.
Figure 3: Formation of endothelial-derived multipotent stem-like cells induced by constitutively active ALK2.
Figure 4: TGF-β2 and BMP4 activate ALK2 and induce EndMT.
Figure 5: Endothelial cells treated with TGF-β2 or BMP4 express mesenchymal stem cell markers and exhibit multipotency.
Figure 6: ALK2 is necessary for EndMT.

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Change history

  • 07 April 2011

     In the version of this article initially published, the flow cytometry plot in Figure 4b corresponding to the condition HCMEC and TGF-β2 was incorrect. This plot has been replaced with the correct one in the HTML and PDF versions of the article.

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Acknowledgements

We thank M. Xu for technical assistance, J. Bischoff (Children's Hospital Boston) for providing primary cultures of human endothelial cells, A. Maidment for X-rays and Y. Mishina (University of Michigan) for providing caALK2-transgenic mice. We also thank E. Hay (Harvard Medical School) for human corneal fibroblasts. This work was supported by grants from the US National Institutes of Health to B.R.O., R.K., F.S.K. and E.M.S. and to the University of Pennsylvania Vector Core. Additional support was from the International Fibrodysplasia Ossificans Progressiva Association, the Ian Cali and the Weldon Family Endowments, the Penn Center for Musculoskeletal Disorders, the Isaac and Rose Nassau Professorship of Orthopaedic Molecular Medicine and the Rita Allen Foundation.

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Authors and Affiliations

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

    Damian Medici & Raghu Kalluri

  2. Department of Orthopaedic Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Eileen M Shore, Vitali Y Lounev & Frederick S Kaplan

  3. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Eileen M Shore

  4. Center for Research in Fibrodysplasia Ossificans Progressiva and Related Disorders, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Eileen M Shore, Vitali Y Lounev & Frederick S Kaplan

  5. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Frederick S Kaplan

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

    Raghu Kalluri

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

    Raghu Kalluri

  8. Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, USA

    Bjorn R Olsen

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  1. Damian Medici
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Contributions

D.M. designed and performed experiments, analyzed data and wrote the manuscript. V.Y.L. performed experiments. E.M.S., F.S.K. and R.K. provided research materials, edited the manuscript and provided technical advice. B.R.O. designed experiments, analyzed data and wrote the manuscript.

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Correspondence to Damian Medici or Bjorn R Olsen.

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Medici, D., Shore, E., Lounev, V. et al. Conversion of vascular endothelial cells into multipotent stem-like cells. Nat Med 16, 1400–1406 (2010). https://doi.org/10.1038/nm.2252

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