Inhibition of T cell protein tyrosine phosphatase enhances IL-18-dependent hematopoietic stem cell expansion (P6268)

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 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 9-fold increase in the number of hematopoietic progenitors in murine bone marrow. This effect could be reproduced using a short (48 h) treatment with a pharmacological inhibitor of TC-PTP in murine bone marrow, as well as in human bone marrow 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 IL-18 signaling pathway, leading to increased production of IL-12 and IFN-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.