We surveyed 16 published and unpublished data sets to determine whether a consistent pattern of transcriptional deregulation in aging murine hematopoietic stem cells (HSC) exists. Despite substantial heterogeneity between individual studies, we uncovered a core and robust HSC aging signature. We detected increased transcriptional activation in aged HSCs, further confirmed by chromatin accessibility analysis. Unexpectedly, using two independent computational approaches, we established that deregulated aging genes consist largely of membrane-associated transcripts, including many cell surface molecules previously not associated with HSC biology. We show that Selp, the most consistent deregulated gene, is not merely a marker for aged HSCs but is associated with HSC functional decline. Additionally, single-cell transcriptomics analysis revealed increased heterogeneity of the aged HSC pool. We identify the presence of transcriptionally "young-like" HSCs in aged bone marrow. We share our results as an online resource and demonstrate its utility by confirming that exposure to sympathomimetics, and deletion of Dnmt3a/b, molecularly resembles HSC rejuvenation or aging, respectively.
Hematopoietic stem cells (HSCs) sustain the lifelong production of all blood cell lineages. The functioning of aged HSCs is impaired, including a declined repopulation capacity and myeloid and platelet-restricted differentiation. Both cell-intrinsic and microenvironmental extrinsic factors contribute to HSC aging. Recent studies highlight the emerging role of inflammation in contributing to HSC aging. In this review, we summarize the recent finding of age-associated changes of HSCs and the bone marrow niche in which they lodge, and discuss how inflammation may drive HSC aging.
Hematopoiesis is finely regulated to enable timely production of the right number and type of mature immune cells to maintain tissue homeostasis. Dysregulated hematopoiesis may compromise antiviral immunity and/or exacerbate immunopathogenesis. Herein, we report an essential and new role of ubiquitin X domain containing gene 3B (UBXN3B) in balancing myelopoiesis and lymphopoiesis. Ubxn3b deficiency (Ubxn3b−/−) results in a remarkable increase in myeloid cells and neutrophil-to-lymphocyte ratio, along with a reduction in lymphocytes in steady-state mice. This dysregulation is exacerbated during viral infection and renders mice highly vulnerable to severe lung pathology induced by severe acute respiratory syndrome coronavirus 2 and arthritis by arthritogenic alphaviruses. Ubxn3b−/− mice present normal type I IFNs, higher viral loads and inflammatory mediators, lower virus-specific immunoglobulin G and slower resolution of disease, when compared to Ubxn3b+/+ littermates. Mechanistically, Ubxn3b−/− mice have fewer multipotent progenitors and common lymphoid progenitors, but more common myeloid progenitors. In particular, the precursor and immature B cell numbers are dramatically decreased in the bone marrow of Ubxn3b−/− mice. These data demonstrate that UBXN3B signaling is essential for restricting viral infection and immunopathogenesis by maintaining hematopoietic homeostasis.
To determine whether a consistent pattern of transcriptional deregulation in aging murine hematopoietic stem cells (HSC) exists, we collected all available transcriptome studies of aged HSCs, adding our own unpublished data. Cross-validation of all datasets identified a core list of consistently differentially expressed genes; the HSC aging signature. Despite heterogeneity between individual studies, the aging signature is robust and has reached saturation. Our analysis also indicates that HSCs become transcriptionally activated upon aging. Unexpectedly, the signature consists largely of membrane-associated transcripts, including many cell surface molecules previously not associated with HSC biology. We validated that Selp, the top aging gene, is not only a marker for aged HSCs but is functionally involved in age-associated HSC functional decline. We share the aging signature as an online resource with the community and demonstrate its value by confirming that exposure to sympathomimetics, and deletion of Dnmt3a/b, molecularly resembles HSC rejuvenation or aging, respectively.
Thrombocytopenia, prevalent in the majority of patients with myeloid malignancies, such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), is an independent adverse prognostic factor. Azacitidine (AZA), a mainstay therapeutic agent for stem cell transplant–ineligible patients with MDS/AML, often transiently induces or further aggravates disease-associated thrombocytopenia by an unknown mechanism. Here, we uncover the critical role of an acute type-I interferon (IFN-I) signaling activation in suppressing megakaryopoiesis in AZA-mediated thrombocytopenia. We demonstrate that megakaryocytic lineage-primed progenitors present IFN-I receptors and, upon AZA exposure, engage STAT1/SOCS1-dependent downstream signaling prematurely attenuating thrombopoietin receptor (TPO-R) signaling and constraining megakaryocytic progenitor cell growth and differentiation following TPO-R stimulation. Our findings directly implicate RNA demethylation and IFN-I signal activation as a root cause for AZA-mediated thrombocytopenia and suggest mitigation of TPO-R inhibitory innate immune signaling as a suitable therapeutic strategy to support platelet production, particularly during the early phases of AZA therapy.
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