title: Pten Cell Autonomously Modulates the Hematopoietic Stem Cell Response to Inflammatory Cytokines.
abstract: 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.
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Box 8220, St. Louis, MO 63110, USA.
authors.forename: Shaina N
authors.initials: SN
authors.lastname: Porter
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Box 8220, St. Louis, MO 63110, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Cluster
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Robert A J
authors.initials: RAJ
authors.lastname: Signer
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Box 8220, St. Louis, MO 63110, USA.
authors.forename: Jenna
authors.initials: J
authors.lastname: Voigtmann
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Box 8220, St. Louis, MO 63110, USA.
authors.forename: Darlene A
authors.initials: DA
authors.lastname: Monlish
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Box 8220, St. Louis, MO 63110, USA.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Schuettpelz
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Box 8220, St. Louis, MO 63110, USA. Electronic address: magee_j@kids.wustl.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Magee
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D005333:Fetus; D005786:Gene Expression Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D016898:Interferon-alpha; D016179:Granulocyte Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse