BST2 facilitates activation of hematopoietic stem cells through ERK signaling.

Exp Hematol

Program in Translational Biology and Molecular Medicine, Graduate School of Biomedical Sciences (GSBS) and Medical Scientist Training Program, Baylor College of Medicine, Houston, TX; Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine and Texas Children's Hospital, Houston, TX; Program in Immunology, GSBS, Baylor College of Medicine, Houston, TX; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX. Electronic address:

Published: December 2024

AI Article Synopsis

  • Interferon gamma (IFNγ) is a proinflammatory cytokine that can cause bone marrow failure by activating and exhausting hematopoietic stem cells (HSCs), with bone marrow stromal antigen 2 (BST2) playing a crucial role in this activation process.
  • Research using a murine model shows that knocking out BST2 doesn't impact immune responses or HSC localization in the bone marrow, but it does affect lipid raft polarity in response to IFNγ.
  • The study concludes that BST2 is essential for HSC division by promoting cell polarization and essential ERK1/2 activation, which could be significant for future cancer and bone marrow failure treatment strategies.

Article Abstract

The proinflammatory cytokine interferon gamma (IFNγ) is upregulated in a variety of infections and contributes to bone marrow failure through hematopoietic stem cell (HSC) activation and subsequent exhaustion. The cell-surface protein, bone marrow stromal antigen 2 (BST2), is a key mediator of this process, because it is induced upon IFN stimulation and required for IFN-dependent HSC activation. To identify the mechanism by which BST2 promotes IFN-dependent HSC activation, we evaluated its role in niche localization, immune cell function, lipid raft formation, and intracellular signaling. Our studies indicated that knockout (KO) of BST2 in a murine model does not disrupt immune cell responses to IFN-inducing mycobacterial infection. Furthermore, intravital imaging studies indicate that BST2 KO does not disrupt localization of HSCs relative to endothelial or osteoblastic niches in the bone marrow. However, using imaging-based flow cytometry, we found that IFNγ treatment shifts the lipid raft polarity of wild-type (WT) but not Bst2 hematopoietic stem and progenitor cells (HSPCs). Furthermore, RNAseq analysis, reverse-phase protein array and western blot analysis of HSPCs indicate that BST2 promotes ERK1/2 phosphorylation during IFNγ-mediated stress. Overall, we find that BST2 facilitates HSC division by promoting cell polarization and ERK activation, thus elucidating a key mechanism of IFN-dependent HSPC activation. These findings inform future approaches in the treatment of cancer and bone marrow failure.

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Source
http://dx.doi.org/10.1016/j.exphem.2024.104653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651051PMC

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