• Open Access

Inhibition of T Cell Protein Tyrosine Phosphatase Enhances Interleukin-18-Dependent Hematopoietic Stem Cell Expansion§

Authors

  • Annie Bourdeau,

    Corresponding author
    1. Sunnybrook Research Institute, Toronto, Ontario, Canada
    2. Department of Immunology, University of Toronto, Toronto, Ontario, Canada
    • Sunnybrook Research Institute, 2075 Bayview Avenue, Platform of Biological Sciences Room S234, Toronto, ON M4N 3M5, Canada
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    • Telephone: 416-480-6100, ext. 3973; Fax: 416-480-5703

  • Sébastien Trop,

    1. Sunnybrook Research Institute, Toronto, Ontario, Canada
    2. Clinician Investigator Program, University of Toronto, Toronto, Ontario, Canada
    3. Division of Cardiac Surgery, St. Michael's Hospital, Toronto, Ontario, Canada
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  • Karen M. Doody,

    1. Rosalind and Morris Goodman Cancer Centre
    2. Department of Biochemistry, McGill University, Montréal, Québec, Canada
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  • Daniel J. Dumont,

    1. Sunnybrook Research Institute, Toronto, Ontario, Canada
    2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
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  • Michel L. Tremblayef

    Corresponding author
    1. Rosalind and Morris Goodman Cancer Centre
    2. Department of Biochemistry, McGill University, Montréal, Québec, Canada
    • Rosalind and Morris Goodman Cancer Centre, 1160 Avenue Des Pins West, Cancer Pavilion, Room 602, Montreal, QC H3A 1A3, Canada
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    • Telephone: 514-398-7290; Fax: 514-398-6769

Errata

This article is corrected by:

  1. Errata: Erratum Volume 31, Issue 6, 1224, Article first published online: 22 May 2013

  • Author contributions: A.B.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; S.T. and K.M.D.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; D.J.D.: data interpretation, manuscript writing; and M.L.T.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

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

  • §

    First published online in STEM CELLSEXPRESS November 8, 2012.

Abstract

The clinical application of hematopoietic progenitor cell-based therapies for the treatment of hematological diseases is hindered by current protocols, which are cumbersome and have limited efficacy to augment the progenitor cell pool. We report that inhibition of T-cell protein tyrosine phosphatase (TC-PTP), an enzyme involved in the regulation of cytokine signaling, through gene knockout results in a ninefold increase in the number of hematopoietic progenitors in murine bone marrow (BM). This effect could be reproduced using a short (48 hours) treatment with a pharmacological inhibitor of TC-PTP in murine BM, as well as in human BM, peripheral blood, and cord blood. We also demonstrate that the ex vivo use of TC-PTP inhibitor only provides a temporary effect on stem cells and did not alter their capacity to reconstitute all hematopoietic components in vivo. We establish that one of the mechanisms whereby inhibition of TC-PTP mediates its effects involves the interleukin-18 (IL-18) signaling pathway, leading to increased production of IL-12 and interferon-gamma by progenitor cells. Together, our results reveal a previously unrecognized role for IL-18 in contributing to the augmentation of the stem cell pool and provide a novel and simple method to rapidly expand progenitor cells from a variety of sources using a pharmacological compound. STEM CELLS2013;31:293–304

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