Systemic Virus Infections Differentially Modulate Cell Cycle State and Functionality of Long-Term Hematopoietic Stem Cells In Vivo

• Published in: Cell reports (Cambridge) Vol. 19; no. 11; pp. 2345 - 2356
• Main Authors: Hirche, Christoph, Frenz, Theresa, Haas, Simon F., Döring, Marius, Borst, Katharina, Tegtmeyer, Pia-K., Brizic, Ilija, Jordan, Stefan, Keyser, Kirsten, Chhatbar, Chintan, Pronk, Eline, Lin, Shuiping, Messerle, Martin, Jonjic, Stipan, Falk, Christine S., Trumpp, Andreas, Essers, Marieke A.G., Kalinke, Ulrich
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13-06-2017; Elsevier
• Subjects: Animals; bone marrow transplantation; Cell Cycle; Cell Proliferation; hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Infection - virology; inflammatory cytokines; Mice; quiescence; Signal Transduction; stem cell activation; stem cell function; systemic inflammation; transplant complications; virus infections; systemic inflammation; transplant complications; stem cell activation; cell cycle; stem cell function; quiescence; inflammatory cytokines; hematopoietic stem cells; bone marrow transplantation; virus infections
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.05.063

Quiescent long-term hematopoietic stem cells (LT-HSCs) are efficiently activated by type I interferon (IFN-I). However, this effect remains poorly investigated in the context of IFN-I-inducing virus infections. Here we report that both vesicular stomatitis virus (VSV) and murine cytomegalovirus (MCMV) infection induce LT-HSC activation that substantially differs from the effects triggered upon injection of synthetic IFN-I-inducing agents. In both infections, inflammatory responses had to exceed local thresholds within the bone marrow to confer LT-HSC cell cycle entry, and IFN-I receptor triggering was not critical for this activation. After resolution of acute MCMV infection, LT-HSCs returned to phenotypic quiescence. However, non-acute MCMV infection induced a sustained inflammatory milieu within the bone marrow that was associated with long-lasting impairment of LT-HSC function. In conclusion, our results show that systemic virus infections fundamentally affect LT-HSCs and that also non-acute inflammatory stimuli in bone marrow donors can affect the reconstitution potential of bone marrow transplants.
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•Acute virus infections activate LT-HSCs independently of IFN-I receptor signaling•A bone marrow-intrinsic inflammatory threshold prevents excessive LT-HSC activation•Non-acute MCMV infection alters the bone marrow milieu and LT-HSC gene expression•Despite the return to phenotypic quiescence, LT-HSCs retain functional deficits
Long-term hematopoietic stem cells (LT-HSCs) are activated by recombinant type I interferon (IFN-I). Hirche et al. report here that acute systemic virus infections activate LT-HSCs independently of IFN-I receptor signaling. Non-acute infection of bone marrow donors impacts LT-HSC function, but not phenotype, potentially explaining clinical complications following bone marrow transplantations.