title: Dexamethasone targeted directly to macrophages induces macrophage niches that promote erythroid expansion.
abstract: Cultures of human CD34(pos) cells stimulated with erythroid growth factors plus dexamethasone, a model for stress erythropoiesis, generate numerous erythroid cells plus a few macrophages (approx. 3%; 3:1 positive and negative for CD169). Interactions occurring between erythroblasts and macrophages in these cultures and the biological effects associated with these interactions were documented by live phase-contrast videomicroscopy. Macrophages expressed high motility interacting with hundreds/thousands of erythroblasts per hour. CD169(pos) macrophages established multiple rapid 'loose' interactions with proerythroblasts leading to formation of transient erythroblastic island-like structures. By contrast, CD169(neg) macrophages established 'tight' interactions with mature erythroblasts and phagocytosed these cells. 'Loose' interactions of CD169(pos) macrophages were associated with proerythroblast cytokinesis (the M phase of the cell cycle) suggesting that these interactions may promote proerythroblast duplication. This hypothesis was tested by experiments that showed that as few as 103 macrophages significantly increased levels of 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide incorporation frequency in S/G2/M and cytokinesis expressed by proerythroblasts over 24 h of culture. These effects were observed also when macrophages were co-cultured with dexamethasone directly conjugated to a macrophage-specific CD163 antibody. In conclusion, in addition to promoting proerythroblast proliferation directly, dexamethasone stimulates expansion of these cells indirectly by stimulating maturation and cytokinesis supporting activity of macrophages.
authors.affiliation: National AIDS Center, New York, NY, USA Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Falchi
authors.affiliation: Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Lilian
authors.initials: L
authors.lastname: Varricchio
authors.affiliation: Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA Hematology/Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Martelli
authors.affiliation: Hematology/Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Masiello
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy Hematology/Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Federici
authors.affiliation: Medicine, Campus Biomedicus, Università La Sapienza, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Zingariello
authors.affiliation: Transfusion Center, Università La Sapienza, Rome, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Girelli
authors.affiliation: Kings County Hospital and Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Whitsett
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
authors.forename: Emanuel F
authors.initials: EF
authors.lastname: Petricoin
authors.affiliation: Department of Biomedicine, University of Aarhus, Aarhus C, Denmark Institute of Molecular Medicine, University of Souther Denmark, Denmark.
authors.forename: Søren Kragh
authors.initials: SK
authors.lastname: Moestrup
authors.affiliation: Hematology/Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Ann
authors.initials: A
authors.lastname: Zeuner
authors.affiliation: Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA Hematology/Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy annarita.migliaccio@mssm.edu.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Migliaccio
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004900:Erythroblasts / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D004920:Erythropoiesis / Q000187:drug effects / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D018715:Microscopy, Video; D059008:Time-Lapse Imaging
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D003907:Dexamethasone