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Cell Rep. 2017 Jun 13;19(11):2345-2356. doi: 10.1016/j.celrep.2017.05.063.

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

Author information

1
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany.
2
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; "Hematopoietic Stem Cells and Stress" Group, German Cancer Research Centre (DKFZ), 69121 Heidelberg, Germany.
3
Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia.
4
Icahn School of Medicine at Mount Sinai, Department of Oncological Sciences, New York, NY 10029, USA.
5
Department of Virology, Hannover Medical School, 30625 Hannover, Germany.
6
Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
7
Institute of Transplant Immunology, IFB-Tx, Hannover Medical School, 30625 Hannover, Germany.
8
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; Division of Stem Cells and Cancer, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany.
9
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany. Electronic address: ulrich.kalinke@twincore.de.

Abstract

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.

KEYWORDS:

bone marrow transplantation; cell cycle; hematopoietic stem cells; inflammatory cytokines; quiescence; stem cell activation; stem cell function; systemic inflammation; transplant complications; virus infections

PMID:
28614719
DOI:
10.1016/j.celrep.2017.05.063
[Indexed for MEDLINE]
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