Inhibition of T cell Protein Tyrosine Phosphatase (TC-PTP) Enhances IL-18-dependent Hematopoietic Progenitor Expansion (111.57)

Abstract

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 expand 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 9-fold expansion of functional hematopoietic progenitors in murine bone marrow (BM). This effect could be reproduced using a short (48 h) 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 BM stem cells treated ex-vivo with a TC-PTP inhibitor can differentiate into functional progeny in vivo. We establish that the mechanism whereby inhibition of TC-PTP mediates its effects involves the IL-18 signaling pathway, leading to increased production of IL-12 and IFN-γ by progenitor cells. Together, our results reveal a previously unrecognized role for IL-18 in regulating progenitor cell expansion, and provide a novel and simple method to rapidly expand progenitor cells from a variety of sources using a pharmacological compound.