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• W4385982912 abstract "Chronic infections are prevalent worldwide and contribute to bone marrow failure syndromes. Our previously published results found chronic interferon-gamma (IFNy) released during infections facilitates hematopoietic stem cell (HSC) proliferative exhaustion by disrupting both quiescence and self-renewal, thereby contributing to bone marrow failure syndromes. Specifically, we found IFN-induced surface protein, Bone Marrow Stromal Antigen 2 (BST2), facilitates HSC activation, and the loss of BST2 protected against the depletion of HSCs during chronic infection. Yet, the mechanism by which BST2 impacts HSCs activation is unknown. To identify the mechanism by which BST2 promotes interferon-dependent HSC activation, we evaluated its role in niche localization, immune cell function, lipid raft formation, and intracellular signaling using BST2-/- mice challenged with Mycobacterium avium. Intravital imaging studies indicated that BST2 does not promote migration of HSCs to activated endothelial or osteoblastic niches in the bone marrow, nor does disruption of BST2 affect immune cell responses to interferon-inducing mycobacterial infection. However, using imaging-based flow cytometry, we found that IFNg treatment shifts the lipid raft polarity of WT but not Bst2-/- hematopoietic stem and progenitor cells (HSPCs). Furthermore, differential gene expression, reverse phase protein array and western blot analysis of HSPCs indicate that BST2 promotes ERK1/2 phosphorylation during IFNg-mediated stress. Overall, we find that BST2 facilitates HSC division by promoting cell polarization and ERK activation, thus elucidating a key mechanism of interferon-dependent HSC activation. These findings inform future approaches in the treatment for patients that suffer from cytopenia, bone marrow failure, and engraftment failure due to high levels of inflammatory stimuli. Chronic infections are prevalent worldwide and contribute to bone marrow failure syndromes. Our previously published results found chronic interferon-gamma (IFNy) released during infections facilitates hematopoietic stem cell (HSC) proliferative exhaustion by disrupting both quiescence and self-renewal, thereby contributing to bone marrow failure syndromes. Specifically, we found IFN-induced surface protein, Bone Marrow Stromal Antigen 2 (BST2), facilitates HSC activation, and the loss of BST2 protected against the depletion of HSCs during chronic infection. Yet, the mechanism by which BST2 impacts HSCs activation is unknown. To identify the mechanism by which BST2 promotes interferon-dependent HSC activation, we evaluated its role in niche localization, immune cell function, lipid raft formation, and intracellular signaling using BST2-/- mice challenged with Mycobacterium avium. Intravital imaging studies indicated that BST2 does not promote migration of HSCs to activated endothelial or osteoblastic niches in the bone marrow, nor does disruption of BST2 affect immune cell responses to interferon-inducing mycobacterial infection. However, using imaging-based flow cytometry, we found that IFNg treatment shifts the lipid raft polarity of WT but not Bst2-/- hematopoietic stem and progenitor cells (HSPCs). Furthermore, differential gene expression, reverse phase protein array and western blot analysis of HSPCs indicate that BST2 promotes ERK1/2 phosphorylation during IFNg-mediated stress. Overall, we find that BST2 facilitates HSC division by promoting cell polarization and ERK activation, thus elucidating a key mechanism of interferon-dependent HSC activation. These findings inform future approaches in the treatment for patients that suffer from cytopenia, bone marrow failure, and engraftment failure due to high levels of inflammatory stimuli." @default.
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• W4385982912 date "2023-01-01" @default.
• W4385982912 modified "2023-10-17" @default.
• W4385982912 title "3192 – DEFINING THE MECHANISMS OF BST2 IN INFLAMMATION-DEPENDENT HEMATOPOIETIC STEM CELL ACTIVATION" @default.
• W4385982912 doi "https://doi.org/10.1016/j.exphem.2023.06.299" @default.
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