Injury-Activated Transforming Growth Factor β Controls Mobilization of Mesenchymal Stem Cells for Tissue Remodeling§

Authors

  • Mei Wan,

    Corresponding author
    1. Department of Orthopaedic SurgeryJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
    • Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    Search for more papers by this author
    • Telephone: 410-502-6598; Fax: 410-502-6414

  • Changjun Li,

    1. Department of Orthopaedic SurgeryJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Search for more papers by this author
  • Gehua Zhen,

    1. Department of Orthopaedic SurgeryJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Search for more papers by this author
  • Kai Jiao,

    1. Department of Orthopaedic SurgeryJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Stomatological College, Fourth Military Medical University, Xi'an, People's Republic of China
    Search for more papers by this author
  • Wenying He,

    1. Department of Orthopaedic SurgeryJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Shihezi Medical Collage, Shihezi Univeristy, Xinjiang, People's Republic of China
    Search for more papers by this author
  • Xiaofeng Jia,

    1. Department of Biomedical EngineeringJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Search for more papers by this author
  • Weishan Wang,

    1. Shihezi Medical Collage, Shihezi Univeristy, Xinjiang, People's Republic of China
    Search for more papers by this author
  • Chenhui Shi,

    1. Shihezi Medical Collage, Shihezi Univeristy, Xinjiang, People's Republic of China
    Search for more papers by this author
  • Qiujuan Xing,

    1. Department of Orthopaedic SurgeryJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
    Search for more papers by this author
  • Yiu-Fai Chen,

    1. Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
    Search for more papers by this author
  • Suzanne Jan De Beur,

    1. Division of Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Search for more papers by this author
  • Bing Yu,

    1. Department of Orthopaedic SurgeryJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Search for more papers by this author
  • Xu Cao

    Corresponding author
    1. Department of Orthopaedic SurgeryJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
    • Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    Search for more papers by this author
    • Telephone: 410-502-6440; Fax: 410-502-6414


  • Author contributions: M.W.: conception and design, financial support, collection and assembly of data, data analysis and interpretation, and manuscript writing, C.L., G.Z., K.J., W.H., X.J., W.W., C.S., Q.X., and B.Y.: provision of study material, collection and assembly of data, Y.-F.C. and S.J.D.B.: data analysis and interpretation; X.C.: conception and design, financial support, data analysis and Interpretation, and manuscript writing.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS August 21, 2012.

Abstract

Upon secretion, transforming growth factor β (TGFβ) is maintained in a sequestered state in extracellular matrix as a latent form. The latent TGFβ is considered as a molecular sensor that releases active TGFβ in response to the perturbations of the extracellular matrix at the situations of mechanical stress, wound repair, tissue injury, and inflammation. The biological implication of the temporal discontinuity of TGFβ storage in the matrix and its activation is obscure. Here, using several animal models in which latent TGFβ is activated in vascular matrix in response to injury of arteries, we show that active TGFβ controls the mobilization and recruitment of mesenchymal stem cells (MSCs) to participate in tissue repair and remodeling. MSCs were mobilized into the peripheral blood in response to vascular injury and recruited to the injured sites where they gave rise to both endothelial cells for re-endothelialization and myofibroblastic cells to form thick neointima. TGFβs were activated in the vascular matrix in both rat and mouse models of mechanical injury of arteries. Importantly, the active TGFβ released from the injured vessels is essential to induce the migration of MSCs, and cascade expression of monocyte chemotactic protein-1 stimulated by TGFβ amplifies the signal for migration. Moreover, sustained high levels of active TGFβ were observed in peripheral blood, and at the same time points following injury, Sca1+CD29+CD11bCD45 MSCs, in which 91% are nestin+ cells, were mobilized to peripheral blood and recruited to the remodeling arteries. Intravenously injection of recombinant active TGFβ1 in uninjured mice rapidly mobilized MSCs into circulation. Furthermore, inhibitor of TGFβ type I receptor blocked the mobilization and recruitment of MSCs to the injured arteries. Thus, TGFβ is an injury-activated messenger essential for the mobilization and recruitment of MSCs to participate in tissue repair/remodeling. STEM CELLS2012;30:2498–2511

Ancillary