Inhibition of T Cell Protein Tyrosine Phosphatase Enhances Interleukin-18-Dependent Hematopoietic Stem Cell Expansion
Inhibition of T Cell Protein Tyrosine Phosphatase Enhances Interleukin-18-Dependent Hematopoietic Stem Cell Expansion
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DOI：
10.1002/stem.1276
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发表时间：
2013-02-01
期刊：
影响因子：
5.2
通讯作者：
Tremblayef, Michel L.
中科院分区：
文献类型：
--
作者：
Bourdeau, Annie;Trop, Sebastien;Tremblayef, Michel L.
基于造血祖细胞的疗法用于治疗血液疾病的临床应用受到当前方案的阻碍，这些方案繁琐且对增加祖细胞库的功效有限。我们报告说，通过基因敲除抑制 T 细胞蛋白酪氨酸磷酸酶 (TC-PTP)（一种参与细胞因子信号传导调节的酶）可导致小鼠骨髓 (BM) 中的造血祖细胞数量增加九倍。使用 TC-PTP 药物抑制剂进行短时间（48 小时）治疗，可以在小鼠 BM 以及人 BM、外周血和脐带血中重现这种效应。我们还证明，TC-PTP 抑制剂的离体使用仅对干细胞产生暂时的影响，并没有改变它们在体内重建所有造血成分的能力。我们确定，抑制 TCPTP 介导其作用的机制之一涉及白细胞介素 18 (IL-18) 信号通路，导致祖细胞产生 IL-12 和干扰素 γ 的增加。总之，我们的结果揭示了 IL-18 在促进干细胞库扩增方面以前未被认识到的作用，并提供了一种新颖且简单的方法来使用药理学化合物快速扩增各种来源的祖细胞。干细胞 2013；31:293-304
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 TCPTP 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 CELLS 2013;31:293-304