Get access

Fracture induced mobilization and incorporation of bone marrow-derived endothelial progenitor cells for bone healing

Authors

  • Tomoyuki Matsumoto,

    1. Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
    2. Department of Orthopedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
    Search for more papers by this author
  • Yutaka Mifune,

    1. Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
    2. Department of Orthopedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
    Search for more papers by this author
  • Atsuhiko Kawamoto,

    1. Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
    Search for more papers by this author
  • Ryosuke Kuroda,

    1. Department of Orthopedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
    Search for more papers by this author
  • Taro Shoji,

    1. Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
    2. Department of Orthopedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
    Search for more papers by this author
  • Hiroto Iwasaki,

    1. Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
    Search for more papers by this author
  • Takahiro Suzuki,

    1. Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
    Search for more papers by this author
  • Akira Oyamada,

    1. Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
    Search for more papers by this author
  • Miki Horii,

    1. Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
    Search for more papers by this author
  • Ayumi Yokoyama,

    1. Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
    Search for more papers by this author
  • Hiromi Nishimura,

    1. Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
    Search for more papers by this author
  • Sang Yang Lee,

    1. Department of Orthopedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
    Search for more papers by this author
  • Masahiko Miwa,

    1. Department of Orthopedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
    Search for more papers by this author
  • Minoru Doita,

    1. Department of Orthopedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
    Search for more papers by this author
  • Masahiro Kurosaka,

    1. Department of Orthopedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
    Search for more papers by this author
  • Takayuki Asahara

    Corresponding author
    1. Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
    2. Department of Regenerative Medicine and Research, Tokai University School of Medicine, Kanagawa, Japan
    • Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, 2-2 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
    Search for more papers by this author

  • T. Matsumoto and Y. Mifune contributed equally to this work.

Abstract

We recently reported that systemic administration of peripheral blood (PB) CD34+ cells, an endothelial progenitor cell (EPC)-enriched population, contributed to fracture healing via vasculogenesis/angiogenesis. However, pathophysiological role of EPCs in fracture healing process has not been fully clarified. Therefore, we investigated the hypothesis whether mobilization and incorporation of bone marrow (BM)-derived EPCs may play a pivotal role in appropriate fracture healing. Serial examinations of Laser doppler perfusion imaging and histological capillary density revealed that neovascularization activity at the fracture site peaked at day 7 post-fracture, the early phase of endochondral ossifification. Fluorescence-activated cell sorting (FACS) analysis demonstrated that the frequency of BM cKit+Sca1+Lineage− (Lin−) cells and PB Sca1+Lin− cells, which are EPC-enriched fractions, significantly increased post-fracture. The Sca1+ EPC-derived vasuculogenesis at the fracture site was confirmed by double immunohistochemistry for CD31 and Sca1. BM transplantation from transgenic donors expressing LacZ transcriptionally regulated by endothelial cell-specific Tie-2 promoter into wild type also provided direct evidence that EPCs contributing to enhanced neovascularization at the fracture site were specifically derived from BM. Animal model of systemic administration of PB Sca1+Lin− Green Fluorescent Protein (GFP)+ cells further confirmed incorporation of the mobilized EPCs into the fracture site for fracture healing. These findings indicate that fracture may induce mobilization of EPCs from BM to PB and recruitment of the mobilized EPCs into fracture sites, thereby augment neovascularization during the process of bone healing. EPCs may play an essential role in fracture healing by promoting a favorable environment through neovascularization in damaged skeletal tissue. J. Cell. Physiol. 215: 234–242, 2008. © 2008 Wiley-Liss, Inc.

Ancillary