Mikael Sigvardsson

Mid Sweden University, Härnösand, Västernorrland, Sweden

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Publications (109)814.34 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Invariant NKT (iNKT) cells display characteristics of both adaptive and innate lymphoid cells (ILCs). Like other ILCs, iNKT cells constitutively express ID proteins, which antagonize the E protein transcription factors that are essential for adaptive lymphocyte development. However, unlike ILCs, ID2 is not essential for thymic iNKT cell development. In this study, we demonstrated that ID2 and ID3 redundantly promoted iNKT cell lineage specification involving the induction of the signature transcription factor PLZF and that ID3 was critical for development of TBET-dependent NKT1 cells. In contrast, both ID2 and ID3 limited iNKT cell numbers by enforcing the postselection checkpoint in conventional thymocytes. Therefore, iNKT cells show both adaptive and innate-like requirements for ID proteins at distinct checkpoints during iNKT cell development.
    The Journal of Immunology 11/2013; · 5.52 Impact Factor
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    ABSTRACT: Transcription factor doses are of importance for normal and malignant B-lymphocyte development, however, the understanding of underlying mechanisms and functional consequences of reduced transcription factor levels are limited. We have analyzed progenitor and B-lineage compartments in mice carrying heterozygote mutations in the E2a, Ebf1 or Pax5 genes. While lymphoid progenitors from Ebf1 or Pax5 heterozygote mice were specified and lineage restricted in a manner comparable to Wt progenitors, this process was severely impaired in E2a heterozygote mutant mice. This defect was not significantly enhanced upon combined deletion of E2a with Ebf1 or Pax5. Analysis of the pre-B cell compartent in Ebf1 heterozygote mice revealed a reduction in pre-B cell numbers. These cells expressed Pax5 and other B-lineage associated genes and global gene expression analysis suggested that the reduction of the pre-B cell compartment was a result of impaired pre-B cell expansion. This idea was supported by a reduction in IL2rα expressing late pre-B cells as well as by cell cycle analysis and by the finding that the complexity of the VDJ rearangement patterns were comparable in Wt and Ebf1+/- pre-B cells even though the number of progenitors were reduced. Heterozygote deletion of Ebf1 resulted in impaired responce to IL7 in vitro and reduced expression levels of pre-BCR on the cell surface providing possible explanations to the observed stage specific redution in cellular expansion. Thus, transcription factor doses are critical for specification as well as expansion of B-lymphoid progenitors, providing an increased insight into the molecular regulation of B-cell development.
    Journal of Biological Chemistry 09/2013; · 4.65 Impact Factor
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    ABSTRACT: Key points Hematopoietic stem cell aging associate with stable transcriptional alterations that persist through transplantation.Somatic cell reprogramming of aged hematopoietic stem and progenitor cells reverses functional defects associated with hematopoietic aging.
    Blood 03/2013; · 9.78 Impact Factor
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    ABSTRACT: The E2A transcription factors promote the development of thymus-seeding cells but it remains unknown whether these proteins play a role in T lymphocyte lineage specification or commitment. Here we showed that E2A proteins were required to promote T lymphocyte commitment from DN2 thymocytes and to extinguish their potential for alternative fates. E2A proteins functioned in DN2 cells to limit expression of Gata3, which encodes an essential T lymphocyte transcription factor whose ectopic expression can arrest T cell differentiation. Genetic, or siRNA-mediated, reduction of Gata3 rescued T cell differentiation in the absence of E2A and restricted the development of alternative lineages by limiting the expanded self-renewal potential in E2A(-/-) DN2 cells. Our data support a novel paradigm in lymphocyte lineage commitment in which the E2A proteins are necessary to limit the expression of an essential lineage specification and commitment factor in order to restrain self-renewal and prevent an arrest in differentiation.
    Blood 01/2013; · 9.78 Impact Factor
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    ABSTRACT: Recent studies have identified a number of transcriptional regulators, including E2A, early B-cell factor 1 (EBF1), FOXO1, and paired box gene 5 (PAX5), that promote early B-cell development. However, how this ensemble of regulators mechanistically promotes B-cell fate remains poorly understood. Here we demonstrate that B-cell development in FOXO1-deficient mice is arrested in the common lymphoid progenitor (CLP) LY6D(+) cell stage. We demonstrate that this phenotype closely resembles the arrest in B-cell development observed in EBF1-deficient mice. Consistent with these observations, we find that the transcription signatures of FOXO1- and EBF1-deficient LY6D(+) progenitors are strikingly similar, indicating a common set of target genes. Furthermore, we found that depletion of EBF1 expression in LY6D(+) CLPs severely affects FOXO1 mRNA abundance, whereas depletion of FOXO1 activity in LY6D(+) CLPs ablates EBF1 transcript levels. We generated a global regulatory network from EBF1 and FOXO1 genome-wide transcription factor occupancy and transcription signatures derived from EBF1- and FOXO1-deficient CLPs. This analysis reveals that EBF1 and FOXO1 act in a positive feedback circuitry to promote and stabilize specification to the B-cell lineage.
    Proceedings of the National Academy of Sciences 12/2012; · 9.81 Impact Factor
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    ABSTRACT: Despite great progress in identification of mesenchymal stem cells (MSCs) from bone marrow (BM), our knowledge on their in vivo cellular identity remains limited. We here report that cells expressing the transcription factor Ebf2 in the adult BM display characteristics of MSCs. The Ebf2(+) cells are highly clonal and physiologically quiescent. In vivo lineage-tracing experiments, single cell clone transplantations and in vitro differentiation assay revealed their self-renewal and multilineage differentiation capacity. Gene expression analysis of the freshly sorted Ebf2(+) cells demonstrated expression of genes previously reported to be associated with MSCs and co-expression of multiple lineage-associated genes in a single cell level. Thus, Ebf2 expression is not restricted to committed osteoblast progenitor cells but rather marks a multipotent mesenchymal progenitor cell population in adult mouse BM. These cells do not appear to be completely overlapping with the previous reported MSC populations. The findings provide new insights into the in vivo cellular identity and molecular properties of BM mesenchymal stem and progenitor cells.
    Molecular and cellular biology 11/2012; · 6.06 Impact Factor
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    ABSTRACT: Human hematopoietic stem cells reside in the CD34+CD38-CD90+ population in cord blood and bone marrow. However, this cell fraction is heterogeneous, and the phenotype of the rare primitive stem cells remains poorly defined. We here report that primitive cord blood CD34+CD38-CD90+ stem cells, with the ability to reconstitute NOD/SCID-IL2Rγ(c) null mice long term, at 24 weeks after transplantation, can be prospectively isolated at an increased purity by using integrin α2 receptor as an additional stem cell marker. Using a limiting dilution transplantation assay, we found a highly significant enrichment of multilineage reconstituting stem cells in the CD34+CD38-CD90+ cell fraction expressing the integrin α2 receptor, with a frequency of 1/29 cells, as compared to a frequency of 1/157 in the corresponding integrin α2- cells. In line with this, long-term reconstituting stem cells within the cord blood CD34+CD38- cell population were significantly enriched in the integrin α2+ fraction, while stem cells and progenitors reconstituting short-term, at 8-12 weeks, were heterogeneous in integrin α2 expression. Global gene expression profiling revealed that the lineage-marker negative (Lin-) CD34+CD38-CD90+CD45RA- integrin α2+ cell population was molecularly distinct from the integrin α2- cell population and the more mature Lin-CD34+CD38-CD90-CD45RA- cell population. Our findings identify integrin α2 as a novel stem cell marker, which improves prospective isolation of the primitive human hematopoietic stem cells within the CD34+CD38-CD90+ cell population for experimental and therapeutic stem cell applications.
    Stem Cells 11/2012; · 7.70 Impact Factor
  • Mikael Sigvardsson
    Blood 11/2012; 120(18):3630-1. · 9.78 Impact Factor
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    ABSTRACT: To better understand the process of B-lymphocyte lineage restriction, we have investigated molecular and functional properties in early B-lineage cells from Pax-5-deficient animals crossed to a B-lineage-restricted reporter mouse, allowing us to identify B-lineage-specified progenitors independently of conventional surface markers. Pax-5 deficiency resulted in a dramatic increase in the frequency of specified progenitor B-cells marked by expression of a λ5 (Igll1) promoter-controlled reporter gene. Gene expression analysis of ex vivo isolated progenitor cells revealed that Pax-5 deficiency has a minor impact on B-cell specification. However, single-cell in vitro differentiation analysis of ex vivo isolated cells revealed that specified B-lineage progenitors still displayed a high degree of plasticity for development into NK or T lineage cells. In contrast, we were unable to detect any major changes in myeloid lineage potential in specified Pax-5-deficient cells. By comparison of gene expression patterns in ex vivo isolated Pax-5- and Ebf-1-deficient progenitors, it was possible to identify a set of B-cell-restricted genes dependent on Ebf-1 but not Pax-5, supporting the idea that B-cell specification and commitment is controlled by distinct regulatory networks.
    Proceedings of the National Academy of Sciences 09/2012; 109(39):15871-6. · 9.81 Impact Factor
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    ABSTRACT: Immune-induced prostaglandin E2 (PGE2) synthesis is critical for fever and other centrally elicited disease symptoms. The production of PGE2 depends on cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES-1), but the identity of the cells involved has been a matter of controversy. We generated mice expressing mPGES-1 either in cells of hematopoietic or nonhematopoietic origin. Mice lacking mPGES-1 in hematopoietic cells displayed an intact febrile response to lipopolysaccharide, associated with elevated levels of PGE2 in the cerebrospinal fluid. In contrast, mice that expressed mPGES-1 only in hematopoietic cells, although displaying elevated PGE2 levels in plasma but not in the cerebrospinal fluid, showed no febrile response to lipopolysaccharide, thus pointing to the critical role of brain-derived PGE2 for fever. Immunohistochemical stainings showed that induced cyclooxygenase-2 expression in the brain exclusively occurred in endothelial cells, and quantitative PCR analysis on brain cells isolated by flow cytometry demonstrated that mPGES-1 is induced in endothelial cells and not in vascular wall macrophages. Similar analysis on liver cells showed induced expression in macrophages and not in endothelial cells, pointing at the distinct role for brain endothelial cells in PGE2 synthesis. These results identify the brain endothelial cells as the PGE2-producing cells critical for immune-induced fever.
    Endocrinology 08/2012; 153(10):4849-61. · 4.72 Impact Factor
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    ABSTRACT: Aging causes profound effects on the hematopoietic stem cell (HSC) pool, including an altered output of mature progeny and enhanced self-propagation of repopulating-defective HSCs. An important outstanding question is whether HSCs can be protected from aging. The signal adaptor protein LNK negatively regulates hematopoiesis at several cellular stages. It has remained unclear how the enhanced sensitivity to cytokine signaling caused by LNK deficiency affects hematopoiesis upon aging. Our findings demonstrate that aged LNK(-/-) HSCs displayed a robust overall reconstitution potential and gave rise to a hematopoietic system with a balanced lineage distribution. Although aged LNK(-/-) HSCs displayed a distinct molecular profile in which reduced proliferation was central, little or no difference in the proliferation of aged LNK(-/-) HSCs was observed after transplantation when compared to aged WT HSCs. This coincided with equal telomere maintenance in WT and LNK(-/-) HSCs. Collectively, our studies suggest that enhanced cytokine signaling can counteract functional age-related HSC decline.
    Aging cell 07/2012; · 7.55 Impact Factor
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    ABSTRACT: HIV-1 infection enhances the expression of inhibitory molecules on T-cells leading to T-cell impairment. The signaling pathways underlying the regulation of inhibitory molecules and subsequent onset of T-cell impairment remains elusive. Herein, we showed that both autologous and allogeneic T-cells exposed to HIV-pulsed dendritic cells (DCs) upregulated cytotoxic T-lymphocyte antigen (CTLA-4), TNF-related apoptosis-inducing ligand (TRAIL), lymphocyte-activation gene-3 (LAG3), T-cell immunoglobulin mucin-3 (TIM-3), CD160, and certain suppression-associated transcription factors, such as B-lymphocyte induced maturation protein-1 (BLIMP-1), deltex homolog 1 (DTX1), and forkhead box P3 (FOXP3), leading to T-cell suppression. This induction was regulated by p38 mitogen-activated protein kinase/signal transducer and activator of transcription-3 (P38MAPK/STAT3) pathways as their blockade significantly abrogated expression of all the inhibitory molecules studied and a subsequent recovery in T-cell proliferation. Neither IL-6, or IL-10 nor growth factors known to activate STAT3 signaling events were responsible for STAT3 activation. Involvement of the P38MAPK/STAT3 pathways was evident as these proteins had a higher level of phosphorylation in the HIV-1 primed cells. Furthermore, blockade of viral CD4 binding and fusion significantly reduced the negative effects DCs imposed on primed T-cells. In conclusion, HIV-1 interaction with DCs modulated their functionality, causing them to trigger the activation of P38MAPK/STAT3 pathway in T-cells, which was responsible for the upregulation of inhibitory molecules.
    Molecular Medicine 07/2012; · 4.47 Impact Factor
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    Hong Qian, Katarina Le Blanc, Mikael Sigvardsson
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    ABSTRACT: Despite significant progress in our understanding of mesenchymal stem cell (MSC) biology during recent years, much of the information is based on experiments using in vitro culture-selected stromal progenitor cells. Therefore, the natural cellular identity of MSCs remains poorly defined. Numerous studies have reported that CD44 expression is one of the characteristics of MSCs in both humans and mice; however, we here have prospectively isolated bone marrow stromal cell subsets from both human and mouse bone marrow by flow cytometry and characterized them by gene expression analysis and function assays. Our data provide functional and molecular evidence suggesting that primary mesenchymal stem and progenitor cells of bone marrow reside in the CD44(-) cell fraction in both mice and humans. The finding that these CD44(-) cells acquire CD44 expression after in vitro culture provides an explanation for the previous misconceptions concerning CD44 expression on MSCs. In addition, the other previous reported MSC markers, including CD73, CD146, CD271, and CD106/VCAM1, are also differentially expressed on those two cell types. Our microarray data revealed a distinct gene expression profile of the freshly isolated CD44(-) cells and the cultured MSCs generated from these cells. Thus, we conclude that bone marrow MSCs physiologically lack expression of CD44, highlighting the natural phenotype of MSCs and opening new possibilities to prospectively isolate MSCs from the bone marrow.
    Journal of Biological Chemistry 05/2012; 287(31):25795-807. · 4.65 Impact Factor
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    ABSTRACT: Multiple transcription factors guide the development of mature functional natural killer (NK) cells, yet little is known about their function. We used global gene expression and genome-wide binding analyses combined with developmental and functional studies to unveil three roles for the ETS1 transcription factor in NK cells. ETS1 functions at the earliest stages of NK cell development to promote expression of critical transcriptional regulators including T-BET and ID2, NK cell receptors (NKRs) including NKp46, Ly49H, and Ly49D, and signaling molecules essential for NKR function. As a consequence, Ets1(-/-) NK cells fail to degranulate after stimulation through activating NKRs. Nonetheless, these cells are hyperresponsive to cytokines and have characteristics of chronic stimulation including increased expression of inhibitory NKRs and multiple activation-associated genes. Therefore, ETS1 regulates a broad gene expression program in NK cells that promotes target cell recognition while limiting cytokine-driven activation.
    Immunity 05/2012; 36(6):921-32. · 19.80 Impact Factor
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    ABSTRACT: Recent studies have identified a number of transcriptional regulators, including E proteins, EBF1, FOXO1, and PAX5, that act together to orchestrate the B-cell fate. However, it still remains unclear as to how they are linked at the earliest stages of B-cell development. Here, we show that lymphocyte development in HEB-ablated mice exhibits a partial developmental arrest, whereas B-cell development in E2A(+/-)HEB(-/-) mice is completely blocked at the LY6D(-) common lymphoid progenitor stage. We show that the transcription signatures of E2A- and HEB-ablated common lymphoid progenitors significantly overlap. Notably, we found that Foxo1 expression was substantially reduced in the LY6D(-) HEB- and E2A-deficient cells. Finally, we show that E2A binds to enhancer elements across the FOXO1 locus to activate Foxo1 expression, linking E2A and FOXO1 directly in a common pathway. In summary, the data indicate that the earliest event in B-cell specification involves the induction of FOXO1 expression and requires the combined activities of E2A and HEB.
    Proceedings of the National Academy of Sciences 10/2011; 108(42):17402-7. · 9.81 Impact Factor
  • Eva Welinder, Josefine Ahsberg, Mikael Sigvardsson
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    ABSTRACT: Even though B-lymphocyte development is one of the best understood models for cell differentiation in the hematopoetic system, recent advances in cell sorting and functional genomics has increased this understanding further. This has suggested that already early lymphoid primed multipotent progenitor cells (LMPPs) express low levels of lymphoid restricted transcripts. The expression of these genes becomes more pronounced when cells enter the FLT-3/IL-7 receptor positive common lymphoid progenitor (CLP) stage. However, the expression of B-lineage specific genes is limited to a B-cell restricted Ly6D surface positive subpopulation of the CLP compartment. The gene expression patterns also reflect differences in lineage potential and while Ly6D negative FLT-3/IL-7 receptor positive cells represents true CLPs with an ability to generate B/T and NK cells, the Ly6D positive cells lack NK cell potential and display a reduced T-cell potential in vivo. These recent findings suggest that the CLP compartment is highly heterogenous and that the point of no return in B-cell development may occur already in B220(-)CD19(-) cells. These findings have allowed for a better understanding of the interplay between transcription factors like EBF-1, PAX-5 and E47, all known as crucial for normal B-cell development. In this review, we aim to provide a comprehensive overview of B-cell fate specification and commitment based on the recent advances in the understanding of molecular networks as well as functional properties of early progenitor populations.
    Seminars in Immunology 09/2011; 23(5):335-40. · 5.93 Impact Factor
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    ABSTRACT: Recent studies have documented genome-wide binding patterns of transcriptional regulators and their associated epigenetic marks in hematopoietic cell lineages. In order to determine how epigenetic marks are established and maintained during developmental progression, we have generated long-term cultures of hematopoietic progenitors by enforcing the expression of the E-protein antagonist Id2. Hematopoietic progenitors that express Id2 are multipotent and readily differentiate upon withdrawal of Id2 expression into committed B lineage cells, thus indicating a causative role for E2A (Tcf3) in promoting the B cell fate. Genome-wide analyses revealed that a substantial fraction of lymphoid and myeloid enhancers are premarked by the poised or active enhancer mark H3K4me1 in multipotent progenitors. Thus, in hematopoietic progenitors, multilineage priming of enhancer elements precedes commitment to the lymphoid or myeloid cell lineages.
    Immunity 09/2011; 35(3):413-25. · 19.80 Impact Factor
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    ABSTRACT: Deficiencies in the IL-7 signaling pathway result in severe disruptions of lymphoid development in adult mice. To understand more about how IL-7 deficiency impacts early lymphoid development, we have investigated lineage restriction events within the common lymphoid progenitor (CLP) compartment in IL-7 knockout mice. This revealed that although IL-7 deficiency had a minor impact on the development of LY6D(-) multipotent CLPs, the formation of the lineage restricted LY6D(+) CLP population was dramatically reduced. This was reflected in a low-level transcription of B-lineage genes as well as in a loss of functional B-cell commitment. The few Ly6D(+) CLPs developed in the absence of IL-7 displayed increased lineage plasticity and low expression of Ebf-1. Absence of Ebf-1 could be linked to increased plasticity because even though Ly6D(+) cells develop in Ebf-1-deficient mice, these cells retain both natural killer and dendritic cell potential. This reveals that IL-7 is essential for normal development of Ly6D(+) CLPs and that Ebf-1 is crucial for lineage restriction in early lymphoid progenitors.
    Blood 06/2011; 118(5):1283-90. · 9.78 Impact Factor
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    ABSTRACT: Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understanding the aging process. Here, using a model carrying a proofreading-defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging, including anemia, lymphopenia, and myeloid lineage skewing. However, in contrast to physiological stem cell aging, rapidly accumulating mitochondrial DNA mutations had little functional effect on the hematopoietic stem cell pool, and instead caused distinct differentiation blocks and/or disappearance of downstream progenitors. These results show that intact mitochondrial function is required for appropriate multilineage stem cell differentiation, but argue against mitochondrial DNA mutations per se being a primary driver of somatic stem cell aging.
    Cell stem cell 05/2011; 8(5):499-510. · 23.56 Impact Factor

Publication Stats

4k Citations
814.34 Total Impact Points

Institutions

  • 2013
    • Mid Sweden University
      Härnösand, Västernorrland, Sweden
  • 2008–2013
    • University of Chicago
      • • Committee on Cancer Biology
      • • Committee on Immunology
      • • Department of Pathology
      Chicago, IL, United States
  • 1993–2013
    • Lund University
      • • Faculty of Medicine
      • • Department of Experimental Medical Science
      • • Department of Immunotechnology
      • • Stem Cell Center
      Lund, Skane, Sweden
  • 2010–2012
    • University of California, San Diego
      • Section of Molecular Biology
      San Diego, California, United States
    • University of Toronto
      • Department of Immunology
      Toronto, Ontario, Canada
  • 2008–2012
    • Linköping University
      • Department of Clinical and Experimental Medicine (IKE)
      Linköping, OEstergoetland, Sweden
  • 1997
    • Howard Hughes Medical Institute
      Maryland, United States