Open AccessInhibition of T Cell Protein Tyrosine Phosphatase Enhances Interleukin‐18‐Dependent Hematopoietic Stem Cell Expansion
Author(s) -
Bourdeau Annie,
Trop Sébastien,
Doody Karen M.,
Dumont Daniel J.,
Tremblayef Michel L.
Publication year - 2013
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.1276
Subject(s) - progenitor cell , biology , stem cell , haematopoiesis , microbiology and biotechnology , stem cell factor , hematopoietic stem cell , interleukin 3 , cytokine , bone marrow , ex vivo , immunology , endothelial stem cell , t cell , in vivo , in vitro , interleukin 21 , biochemistry , immune system
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. S TEM C ELLS 2013;31:293–304