Pten Cell Autonomously Modulates the Hematopoietic Stem Cell Response to Inflammatory Cytokines.
Pten Cell Autonomously Modulates the Hematopoietic Stem Cell Response to Inflammatory Cytokines.
复制标题
Pten 细胞自主调节造血干细胞对炎症细胞因子的反应。
DOI：
10.1016/j.stemcr.2016.04.008
复制
发表时间：
2016-06-14
影响因子：
5.9
通讯作者：
Magee JA
中科院分区：
文献类型：
--
作者：
Porter SN;Cluster AS;Signer RAJ;Voigtmann J;Monlish DA;Schuettpelz LG;Magee JA
Pten负调节磷脂酰肌醇3-激酶（PI 3 K）途径，并且是维持静止的成体造血干细胞（HSC）所需的。Pten被认为是细胞自主和非细胞自主调控造血干细胞的重要机制，但各机制的相对重要性尚未得到直接验证。此外，激活Pten上游的PI 3 K途径的细胞因子尚未明确。我们试图阐明Pten细胞自主或非细胞自主调节HSC动员。我们还检测了Pten缺乏是否影响HSC对粒细胞集落刺激因子（G-CSF）和干扰素-α（IFNα）的反应，因为这些细胞因子分别诱导HSC动员或增殖。我们表明，Pten调节HSC的动员和扩张，主要是通过细胞自主机制在脾脏。Pten缺陷型HSC不需要G-CSF来动员，尽管它们对甚至低剂量的外源性G-CSF超敏。Pten缺陷型HSC对IFNα的敏感性相似。因此，Pten调节HSC对炎性细胞因子的反应。Pten主要通过细胞自主机制调节HSC动员Pten调节HSC对G-CSF的反应Pten调节HSC对干扰素-α的反应Magee和同事表明，Pten主要通过细胞自主机制抑制HSC动员和髓外扩张。作者还表明，Pten缺陷的HSC对G-CSF和干扰素-α的动员作用非常敏感，即使在低细胞因子浓度下也是如此。这些发现表明Pten在HSC中的关键功能是钝化炎性细胞因子下游的信号转导。
Pten negatively regulates the phosphatidylinositol 3-kinase (PI3K) pathway and is required to maintain quiescent adult hematopoietic stem cells (HSCs). Pten has been proposed to regulate HSCs cell autonomously and non-cell autonomously, but the relative importance of each mechanism has not been directly tested. Furthermore, the cytokines that activate the PI3K pathway upstream of Pten are not well defined. We sought to clarify whether Pten cell autonomously or non-cell autonomously regulates HSC mobilization. We also tested whether Pten deficiency affects the HSC response to granulocyte colony-stimulating factor (G-CSF) and interferon-α (IFNα) since these cytokines induce HSC mobilization or proliferation, respectively. We show that Pten regulates HSC mobilization and expansion in the spleen primarily via cell-autonomous mechanisms. Pten-deficient HSCs do not require G-CSF to mobilize, although they are hyper-sensitized to even low doses of exogenous G-CSF. Pten-deficient HSCs are similarly sensitized to IFNα. Pten therefore modulates the HSC response to inflammatory cytokines. Pten regulates HSC mobilization primarily via cell-autonomous mechanisms Pten modulates the HSC response to G-CSF Pten modulates the HSC response to interferon-α Magee and colleagues show that Pten suppresses HSC mobilization and extramedullary expansion primarily through cell-autonomous mechanisms. The authors also show that Pten-deficient HSCs are hyper-sensitive to mobilizing effects of G-CSF and interferon-α, even at low-cytokine concentrations. These findings suggest that a key function of Pten in HSCs is to blunt signal transduction downstream of inflammatory cytokines.