title: Inhibition of T cell protein tyrosine phosphatase enhances interleukin-18-dependent hematopoietic stem cell expansion.
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.
authors.affiliation: Sunnybrook Research Institute, Toronto, Ontario, Canada. annie.bourdeau@sri.utoronto.ca
authors.forename: Annie
authors.initials: A
authors.lastname: Bourdeau
authors.forename: Sébastien
authors.initials: S
authors.lastname: Trop
authors.forename: Karen M
authors.initials: KM
authors.lastname: Doody
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Dumont
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblayef
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics* / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D053778:Thiazolidines / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D020382:Interleukin-18; D034741:RNA, Small Interfering; D053778:Thiazolidines; D018664:Interleukin-12; D007371:Interferon-gamma; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; C516653:Ptpn2 protein, mouse