• Open Access

Inhibition of Plasminogen Activator Inhibitor Type-1 Activity Enhances Rapid and Sustainable Hematopoietic Regeneration

Authors

  • Abd Aziz Ibrahim,

    1. Division of Hematopoiesis, Research Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
    2. Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
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  • Takashi Yahata,

    Corresponding author
    1. Division of Hematopoiesis, Research Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
    2. Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
    • Correspondence: Takashi Yahata, Ph.D., Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan. Telephone: 81-463-1121; Fax: 81-463-92-4750; e-mail: yahata@is.icc.u-tokai.ac.jp; or Kiyoshi Ando, M.D., Ph.D., Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan. Telephone: 81-463-1121; Fax: 81–463-92-4750; e-mail: andok@keyaki.cc.u-tokai.ac.jp

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  • Makoto Onizuka,

    1. Division of Hematopoiesis, Research Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
    2. Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
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  • Takashi Dan,

    1. Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
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  • Charles Van Ypersele De Strihou,

    1. Service de Nephrologie, Universite Catholique de Louvain, Brussels, Belgium
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  • Toshio Miyata,

    1. Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
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  • Kiyoshi Ando

    Corresponding author
    1. Division of Hematopoiesis, Research Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
    2. Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
    • Correspondence: Takashi Yahata, Ph.D., Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan. Telephone: 81-463-1121; Fax: 81-463-92-4750; e-mail: yahata@is.icc.u-tokai.ac.jp; or Kiyoshi Ando, M.D., Ph.D., Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan. Telephone: 81-463-1121; Fax: 81–463-92-4750; e-mail: andok@keyaki.cc.u-tokai.ac.jp

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Abstract

The prognosis of patients undergoing hematopoietic stem cell transplantation (HSCT) depends on the rapid recovery and sustained life-long hematopoiesis. The activation of the fibrinolytic pathway promotes hematopoietic regeneration; however, the role of plasminogen activator inhibitor-1 (PAI-1), a negative regulator of the fibrinolytic pathway, has not yet been elucidated. We herein demonstrate that bone marrow (BM) stromal cells, especially osteoblasts, produce PAI-1 in response to myeloablation, which negatively regulates the hematopoietic regeneration in the BM microenvironment. Total body irradiation in mice dramatically increased the local expression levels of fibrinolytic factors, including tissue-type plasminogen activator (tPA), plasmin, and PAI-1. Genetic disruption of the PAI-1 gene, or pharmacological inhibition of PAI-1 activity, significantly improved the myeloablation-related mortality and promoted rapid hematopoietic recovery after HSCT through the induction of hematopoiesis-promoting factors. The ability of a PAI-1 inhibitor to enhance hematopoietic regeneration was abolished when tPA-deficient mice were used as recipients, thus indicating that PAI-1 represses tPA-dependent hematopoietic regeneration. The PAI-1 inhibitor not only accelerated the expansion of the donor HSCs during the early-stage of regeneration, but also supported long-term hematopoiesis. Our results indicate that the inhibition of PAI-1 activity could be a therapeutic approach to facilitate the rapid recovery and sustained hematopoiesis after HSCT. Stem Cells 2014;32:946–958

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