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

Published on Jun 1, 2017in Cell Reports7.82
· DOI :10.1016/j.celrep.2017.05.063
Christoph Hirche2
Estimated H-index: 2
(MHH: Hannover Medical School),
Theresa Frenz10
Estimated H-index: 10
(MHH: Hannover Medical School)
+ 15 AuthorsUlrich Kalinke35
Estimated H-index: 35
(MHH: Hannover Medical School)
Cite
Abstract
Summary 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.
  • References (47)
  • Citations (10)
Cite
References47
Newest
Published on Oct 1, 2015in Cell Stem Cell21.46
Simon Haas10
Estimated H-index: 10
,
Jenny Hansson12
Estimated H-index: 12
(EMBL-EBI: European Bioinformatics Institute)
+ 17 AuthorsMarieke Essers10
Estimated H-index: 10
Infections are associated with extensive platelet consumption, representing a high risk for health. However, the mechanism coordinating the rapid regeneration of the platelet pool during such stress conditions remains unclear. Here, we report that the phenotypic hematopoietic stem cell (HSC) compartment contains stem-like megakaryocyte-committed progenitors (SL-MkPs), a cell population that shares many features with multipotent HSCs and serves as a lineage-restricted emergency pool for inflammat...
Published on May 1, 2015in Leukemia9.94
Aoi Jo3
Estimated H-index: 3
,
Sachiyo Mitani6
Estimated H-index: 6
+ 11 AuthorsDaisuke Tomizawa5
Estimated H-index: 5
High expression of EVI1 and MEL1 is a compelling poor prognostic marker of pediatric AML
Published on Apr 1, 2015in Nature Reviews Immunology44.02
Josh Crouse7
Estimated H-index: 7
,
Ulrich Kalinke35
Estimated H-index: 35
,
Annette Oxenius55
Estimated H-index: 55
Type I interferons (IFNs) have both direct and indirect effects on T cells, and can promote or inhibit their antiviral activity. As reviewed here, the outcome of type I IFN signalling in T cells largely depends on the timing of the signal relative to T cell receptor activation.
Published on Apr 1, 2015in Nature43.07
Dagmar Walter4
Estimated H-index: 4
,
Amelie Lier8
Estimated H-index: 8
+ 21 AuthorsPaul Kaschutnig2
Estimated H-index: 2
(DKFZ: German Cancer Research Center)
Here, DNA damage is shown to occur as a direct consequence of inducing haematopoietic stem cells to exit quiescence in response to conditions of stress; in mice with mutations modelling those seen in Fanconi anaemia, this leads to a complete collapse of the haematopoietic system.
Published on Mar 1, 2015in Trends in Immunology13.00
Hans Heinrich Hoffmann5
Estimated H-index: 5
(Rockefeller University),
William M. Schneider9
Estimated H-index: 9
(Rockefeller University),
Catherine M. Rice131
Estimated H-index: 131
(Rockefeller University)
Over half a century has passed since interferons (IFNs) were discovered and shown to inhibit virus infection in cultured cells. Since then, researchers have steadily brought to light the molecular details of IFN signaling, catalogued their pleiotropic effects on cells, and harnessed their therapeutic potential for a variety of maladies. While advances have been plentiful, several fundamental questions have yet to be answered and much complexity remains to be unraveled. We explore the current kno...
Published on Nov 1, 2014in Stem Cells5.61
Katie Matatall3
Estimated H-index: 3
(Center for Cell and Gene Therapy),
Ching-Chieh Shen1
Estimated H-index: 1
(WashU: Washington University in St. Louis)
+ 1 AuthorsKatherine Y. King12
Estimated H-index: 12
(Center for Cell and Gene Therapy)
Interferon gamma (IFNγ) promotes cell division of hematopoietic stem cells (HSCs) without affecting the total HSC number. We postulated that IFNγ stimulates differentiation of HSCs as part of the innate immune response. Here, we report that type II interferon signaling is required, both at baseline and during an animal model of LCMV infection, to maintain normal myeloid development. By separately evaluating myeloid-biased and lymphoid-biased HSC subtypes, we found that myeloid-biased HSCs expres...
Published on Oct 1, 2014in Oncogene6.63
Tomohiko Sato16
Estimated H-index: 16
,
Susumu Goyama23
Estimated H-index: 23
+ 12 AuthorsMasahiro Nakagawa25
Estimated H-index: 25
Relapse of chronic myeloid leukemia (CML) is triggered by stem cells with a reconstituting capacity similar to that of hematopoietic stem cells (HSCs) and CML stem cells are a source of resistance in drug therapy with tyrosine kinase inhibitors (TKIs). Ecotropic viral integration site 1 (EVI1), a key transcription factor in HSC regulation, is known to predict poor outcomes in myeloid malignancies, however, incapability of prospective isolation of EVI1-high leukemic cells precludes the functional...
Published on Oct 1, 2014in Cell Stem Cell21.46
Nina Cabezas-Wallscheid9
Estimated H-index: 9
,
Daniel Klimmeck9
Estimated H-index: 9
(EMBL-EBI: European Bioinformatics Institute)
+ 21 AuthorsSimon Renders4
Estimated H-index: 4
In this study, we present integrated quantitative proteome, transcriptome, and methylome analyses of hematopoietic stem cells (HSCs) and four multipotent progenitor (MPP) populations. From the characterization of more than 6,000 proteins, 27,000 transcripts, and 15,000 differentially methylated regions (DMRs), we identified coordinated changes associated with early differentiation steps. DMRs show continuous gain or loss of methylation during differentiation, and the overall change in DNA methyl...
Published on Feb 20, 2014in PLOS Pathogens6.46
Franziska Dağ5
Estimated H-index: 5
,
Lars Dölken26
Estimated H-index: 26
(University of Cambridge)
+ 15 AuthorsColin Davenport17
Estimated H-index: 17
Herpesviruses establish a lifelong latent infection posing the risk for virus reactivation and disease. In cytomegalovirus infection, expression of the major immediate early (IE) genes is a critical checkpoint, driving the lytic replication cycle upon primary infection or reactivation from latency. While it is known that type I interferon (IFN) limits lytic CMV replication, its role in latency and reactivation has not been explored. In the model of mouse CMV infection, we show here that IFNβ blo...
Published on Feb 10, 2014in Journal of Experimental Medicine10.89
Eric M. Pietras7
Estimated H-index: 7
(UCSF: University of California, San Francisco),
Ranjani Lakshminarasimhan2
Estimated H-index: 2
(UCSF: University of California, San Francisco)
+ 4 AuthorsEmmanuelle Passegué34
Estimated H-index: 34
(UCSF: University of California, San Francisco)
Type I interferons (IFN-1s) are antiviral cytokines that suppress blood production while paradoxically inducing hematopoietic stem cell (HSC) proliferation. Here, we clarify the relationship between the proliferative and suppressive effects of IFN-1s on HSC function during acute and chronic IFN-1 exposure. We show that IFN-1–driven HSC proliferation is a transient event resulting from a brief relaxation of quiescence-enforcing mechanisms in response to acute IFN-1 exposure, which occurs exclusiv...
Cited By10
Newest
Published on Mar 26, 2019in Viruses3.81
Christelle Langevin15
Estimated H-index: 15
,
Christelle Langevin1
Estimated H-index: 1
(Université Paris-Saclay)
+ 0 AuthorsBertrand Collet (Université Paris-Saclay)
The overarching structure of the type I interferon (IFN) system is conserved across vertebrates. However, the variable numbers of whole genome duplication events during fish evolution offer opportunities for the expansion, diversification, and new functionalization of the genes that are involved in antiviral immunity. In this review, we examine how fish models provide new insights about the implication of virus-driven inflammation in immunity and hematopoiesis. Mechanisms that have been discover...
Published on Mar 1, 2019in Stem Cells5.61
Li‐Jie Zhang1
Estimated H-index: 1
(Capital Medical University),
Cen Yan (Capital Medical University)+ 5 AuthorsYuanbo Feng20
Estimated H-index: 20
(Katholieke Universiteit Leuven)
Published on Feb 1, 2019in Cell Reports7.82
Riem Gawish (University of Veterinary Medicine Vienna), Tanja Bulat (University of Veterinary Medicine Vienna)+ 21 AuthorsRita Rom2
Estimated H-index: 2
(University of Veterinary Medicine Vienna)
Summary Cytomegalovirus (CMV) has a high prevalence worldwide, is often fatal for immunocompromised patients, and causes bone marrow suppression. Deficiency of signal transducer and activator of transcription 1 (STAT1) results in severely impaired antiviral immunity. We have used cell-type restricted deletion of Stat1 to determine the importance of myeloid cell activity for the defense against murine CMV (MCMV). We show that myeloid STAT1 limits MCMV burden and infection-associated pathology in ...
Published on Feb 1, 2019in Scandinavian Journal of Immunology2.56
Sonia Simonetti1
Estimated H-index: 1
(National Research Council),
Ambra Natalini1
Estimated H-index: 1
(National Research Council)
+ 4 AuthorsFrancesca Di Rosa3
Estimated H-index: 3
(National Research Council)
Published on Jan 1, 2019
Roland Jurecic17
Estimated H-index: 17
(UM: University of Miami)
Hematopoietic stem cells (HSCs) maintain lifelong production of mature blood cells and regenerate the hematopoietic system after cytotoxic injury. Use of expanding cell surface marker panels and advanced functional analyses have revealed the presence of several immunophenotypically different HSC subsets with distinct self-renewal and repopulating capacity and bias toward selective lineage differentiation. This chapter summarizes current understanding of the phenotypic and functional heterogeneit...
Published on Dec 1, 2018in Cell Stem Cell21.46
Carolina Petrillo4
Estimated H-index: 4
(UniSR: Vita-Salute San Raffaele University),
Lucy G. Thorne2
Estimated H-index: 2
(UCL: University College London)
+ 13 AuthorsMahdad Noursadeghi25
Estimated H-index: 25
(UCL: University College London)
Summary Innate immune factors may restrict hematopoietic stem cell (HSC) genetic engineering and contribute to broad individual variability in gene therapy outcomes. Here, we show that HSCs harbor an early, constitutively active innate immune block to lentiviral transduction that can be efficiently overcome by cyclosporine H (CsH). CsH potently enhances gene transfer and editing in human long-term repopulating HSCs by inhibiting interferon-induced transmembrane protein 3 (IFITM3), which potently...
Published on Dec 1, 2018in Scientific Reports4.01
Felix R. Stahl4
Estimated H-index: 4
,
Roman Jung14
Estimated H-index: 14
(UHH: University of Hamburg)
+ 10 AuthorsMartin Messerle34
Estimated H-index: 34
(MHH: Hannover Medical School)
Mouse models are important and versatile tools to study mechanisms and novel therapies of human disease in vivo. Both, the number and the complexity of murine models are constantly increasing and modification of genes of interest as well as any exogenous challenge may lead to unanticipated biological effects. Laboratory diagnostics of blood samples provide a comprehensive and rapid screening for multiple organ function and are fundamental to detect human disease. Here, we adapt an array of labor...
Published on Aug 14, 2018in bioRxiv
Sonia Simonetti1
Estimated H-index: 1
(Sapienza University of Rome),
Ambra Natalini1
Estimated H-index: 1
(Sapienza University of Rome)
+ 4 AuthorsFrancesca Di Rosa3
Estimated H-index: 3
(National Research Council)
Although clonal expansion is a hallmark of adaptive immunity, the location(s) where antigen-responding T cells enter cell cycle and complete it have been poorly explored. This lack of knowledge stems partially from the limited experimental approaches available. By using Ki67 plus DNA staining and a novel data analysis technique, we distinguished antigen-specific CD8 T cells in G0, in G1, and in S-G2-M phases after intramuscular vaccination of BALB/c mice with antigen-expressing viral vectors. We...
Published on Jul 1, 2018in Immunity21.52
Marko Šestan4
Estimated H-index: 4
(University of Rijeka),
Sonja Marinović2
Estimated H-index: 2
(University of Rijeka)
+ 8 AuthorsFelix M. Wensveen18
Estimated H-index: 18
(University of Rijeka)
Summary Pro-inflammatory cytokines of a T helper-1-signature are known to promote insulin resistance (IR) in obesity, but the physiological role of this mechanism is unclear. It is also unknown whether and how viral infection induces loss of glycemic control in subjects at risk for developing diabetes mellitus type 2 (DM2). We have found in mice and humans that viral infection caused short-term systemic IR. Virally-induced interferon-γ (IFN-γ) directly targeted skeletal muscle to downregulate th...
Published on May 1, 2018in Cell Stem Cell21.46
Simon Haas10
Estimated H-index: 10
,
Andreas Trumpp49
Estimated H-index: 49
,
Michael D. Milsom16
Estimated H-index: 16
Blood and immune cells derive from multipotent hematopoietic stem cells (HSCs). Classically, stem and progenitor populations have been considered discrete homogeneous populations. However, recent technological advances have revealed significant HSC heterogeneity, with evidence for early HSC lineage segregation and the presence of lineage-biased HSCs and lineage-restricted progenitors within the HSC compartment. These and other findings challenge many aspects of the classical view of HSC biology....
View next paperHematopoietic cell derived interferon controls viral replication and virus-induced disease