Pten Cell Autonomously Modulates the Hematopoietic Stem Cell Response to Inflammatory Cytokines

• Main Authors: Shaina N. Porter, Andrew S. Cluster, Robert A.J. Signer, Jenna Voigtmann, Darlene A. Monlish, Laura G. Schuettpelz, Jeffrey A. Magee
• Format: Article
• Language: English
• Published: Elsevier 2016-06-01
• Series: Stem Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2213671116300339

Summary: 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. : 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.