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  • 1.
    Adolfsson, J
    et al.
    Lund University.
    Månsson, R
    Lund University.
    Buza-Vidas, N
    Lund University.
    Hultquist, A
    Lund University.
    Liuba, K
    Lund University.
    Jensen, C T
    Lund University.
    Bryder, D
    Lund University.
    Yang, L
    Lund University.
    Borge, O-J
    Lund University.
    Thoren, L A M
    Lund University.
    Anderson, K
    Lund University.
    Sitnicka, E
    Lund University.
    Sasaki, Y
    Lund University.
    Sigvardsson, Mikael
    Lund University.
    Jacobsen, S E W
    Lund University.
    Identification of Flt3(+) lympho-myeloid stem cells lacking erythro-megakaryocytic potential: A revised road map for adult blood lineage commitment2005In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 121, no 2, p. 295-306Article in journal (Refereed)
    Abstract [en]

    All blood cell lineages derive from a common hematopoietic stem cell (HSC). The current model implicates that the first lineage commitment step of adult pluripotent HSCs results in a strict separation into common lymphoid and common myeloid precursors. We present evidence for a population of cells which, although sustaining a high proliferative and combined lympho-myeloid differentiation potential, have lost the ability to adopt erythroid and megakaryocyte lineage fates. Cells in the Lin-Sca-1+c-kit+ HSC compartment coexpressing high levels of the tyrosine kinase receptor Flt3 sustain granulocyte, monocyte, and B and T cell potentials but in contrast to Lin-Sca-1(+)ckit(+)Flt3(-) HSCs fail to produce significant erythroid and megakaryocytic progeny. This distinct lineage restriction site is accompanied by downregulation of genes for regulators of erythroid and megakaryocyte development. In agreement with representing a lymphoid primed progenitor, Lin(-)Sca-l(+)c-kit(+)CD34(+)Flt3(+) cells display upregulated IL-7 receptor gene expression. Based on these observations, we propose a revised road map for adult blood lineage development.

  • 2. Anderson, Kristina
    et al.
    Rusterholz, Corinne
    Månsson, Robert
    Jensen, Christina T
    Bacos, Karl
    Sasan, Zandi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Sasaki, Yutaka
    Nerlov, Claus
    Sigvardsson, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Jacobsen, Sten Eirik W
    Ectopic expression of PAX5 promotes maintenance of biphenotypic myeloid progenitors coexpressing myeloid and B-cell lineage-associated genes2007In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 109, no 9, p. 3697-3705Article in journal (Refereed)
    Abstract [en]

    The transcription factor PAX5 is a critical regulator of B-cell commitment and development. Although normally not expressed in myeloid progenitors, PAX5 has recently been shown to be frequently expressed in myeloid malignancies and to suppress expression of myeloid differentiation genes, compatible with an effect on the differentiation or maintenance of myeloid progenitors. However, previous studies in which PAX5 was ectopically expressed in normal myeloid progenitors in vivo and in vitro provided conflicting results as to the effect of PAX5 on myeloid development. Herein, we demonstrate that on ectopic expression of PAX5 in bone marrow multipotent stem/progenitor cells, cells with a biphenotypic B220+GR-1/MAC-1+ phenotype are produced. These remain cytokine-dependent, but unlike control-transduced cells they sustain long-term generation of myeloid progenitors in vitro and remain capable of myeloid differentiation. Notably, PAX5+B220+GR-1/MAC- 1+ myeloid progenitors coexpress, at the single-cell level, myeloid genes and otherwise B-cell-specific PAX5 target genes. These findings establish that ectopic expression of PAX5 introduces extensive self-renewal properties in otherwise short-lived myeloid progenitors. Along with the established ectopic expression of PAX5 in acute myeloid leukemia, this motivates a careful investigation of the potential involvement of ectopic PAX5 expression in myeloid and biphenotypic leukemias. © 2007 by The American Society of Hematology.

  • 3.
    Beerman, Isabel
    et al.
    Childrens Hospital Boston.
    Bhattacharya, Deepta
    Washington University.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Weissman, Irving L
    Stanford University.
    Bryder, David
    Lund University.
    Rossi, Derrick J
    Childrens Hospital Boston.
    Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion2010In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, ISSN 0027-8424, Vol. 107, no 12, p. 5465-5470Article in journal (Refereed)
    Abstract [en]

    Aging of the hematopoietic stem cell compartment is believed to contribute to the onset of a variety of age-dependent blood cell pathophysiologies. Mechanistic drivers of hematopoietic stem cell (HSC) aging include DNA damage accumulation and induction of tumor suppressor pathways that combine to reduce the regenerative capacity of aged HSCs. Such mechanisms do not however account for the change in lymphoid and myeloid lineage potential characteristic of HSC aging, which is believed to be central to the decline of immune competence and predisposition to myelogenous diseases in the elderly. Here we have prospectively isolated functionally distinct HSC clonal subtypes, based on cell surface phenotype, bearing intrinsically different capacities to differentiate toward lymphoid and myeloid effector cells mediated by quantitative differences in lineage priming. Finally, we present data supporting a model in which clonal expansion of a class of intrinsically myeloid-biased HSCs with robust self-renewal potential is a central component of hematopoietic aging.

  • 4.
    Bilke, S
    et al.
    Lund University.
    Breslin, T
    Lund University.
    Sigvardsson, Mikael
    The Laboratory for Cell Differentiation Studies, Department for Stem Cell Biology, BMC B12, Lund.
    Probabilistic estimation of microarray data reliability and underlying gene expression2003In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 4, no 40Article in journal (Refereed)
    Abstract [en]

    Background: The availability of high throughput methods for measurement of mRNA concentrations makes the reliability of conclusions drawn from the data and global quality control of samples and hybridization important issues. We address these issues by an information theoretic approach, applied to discretized expression values in replicated gene expression data. Results: Our approach yields a quantitative measure of two important parameter classes: First, the probability P(sigma|S) that a gene is in the biological state sigma in a certain variety, given its observed expression S in the samples of that variety. Second, sample specific error probabilities which serve as consistency indicators of the measured samples of each variety. The method and its limitations are tested on gene expression data for developing murine B-cells and a t-test is used as reference. On a set of known genes it performs better than the t-test despite the crude discretization into only two expression levels. The consistency indicators, i.e. the error probabilities, correlate well with variations in the biological material and thus prove efficient. Conclusions: The proposed method is effective in determining differential gene expression and sample reliability in replicated microarray data. Already at two discrete expression levels in each sample, it gives a good explanation of the data and is comparable to standard techniques.

  • 5.
    Bryder, David
    et al.
    Lund University.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Shaping up a lineage-lessons from B lymphopoesis2010In: CURRENT OPINION IN IMMUNOLOGY, ISSN 0952-7915, Vol. 22, no 2, p. 148-153Article, review/survey (Refereed)
    Abstract [en]

    Even though the development of B lymphoid cells from hematopoietic stem cells is one of the most carefully investigated models of cell differentiation in adult mammalians, a set of recent findings has to a large extent increased our understanding for how B lymphoid commitment is achieved. These include the identification of IKAROS, PU.1 and E2A as transcription factors responsible for lymphoid lineage priming in multipotent cells, as well as the identification of EBF1 dependent B lineage restricted progenitors among cells lacking expression of the classical B lineage markers CD19 or 8220. The insight that the B cell identity may be defined at an earlier stage then previously thought, allows for an increased understanding of B lymphoid development likely to unravel molecular mechanisms of high relevance also for other differentiation processes within as well as outside of the hematopoietic system.

  • 6.
    C. Lin, Yin
    et al.
    University of California San Diego.
    Jhunjhunwala, Suchit
    University of California San Diego.
    Benner, Christopher
    University of California San Diego.
    Heinz, Sven
    University of California San Diego.
    Welinder, Eva
    University of California San Diego.
    Mansson, Robert
    University of California San Diego.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Hagman, James
    National Jewish Health, Denver.
    A. Espinoza, Celso
    University of California San Diego.
    Dutkowski, Janusz
    University of California San Diego.
    Ideker, Trey
    University of California San Diego.
    Glass, Christopher K.
    University of California San Diego.
    Murre, Cornelis
    University of California San Diego.
    A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate2010In: Nature Immunology, ISSN 1529-2908, E-ISSN 1529-2916, Vol. 11, no 7, p. 635-U109Article in journal (Refereed)
    Abstract [en]

    It is now established that the transcription factors E2A, EBF1 and Foxo1 have critical roles in B cell development. Here we show that E2A and EBF1 bound regulatory elements present in the Foxo1 locus. E2A and EBF1, as well as E2A and Foxo1, in turn, were wired together by a vast spectrum of cis-regulatory sequences. These associations were dynamic during developmental progression. Occupancy by the E2A isoform E47 directly resulted in greater abundance, as well as a pattern of monomethylation of histone H3 at lysine 4 (H3K4) across putative enhancer regions. Finally, we divided the pro-B cell epigenome into clusters of loci with occupancy by E2A, EBF and Foxo1. From this analysis we constructed a global network consisting of transcriptional regulators, signaling and survival factors that we propose orchestrates B cell fate.

  • 7.
    Che, Karlhans Fru
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Shankar, Esaki M
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Sundaram, Muthu
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Messmer, Davorka
    Moores Cancer Center, University of California San Diego, La Jolla, USA.
    Bhardwa, N
    New York University School of Medicine, New York, NY, USA.
    Lifson, Jeffrey D
    AIDS and Cancer Virus Program SAIC Frederick Inc., National Cancer Institute at Frederick, Maryland, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Cross Talk between P38MAPK and STAT3 Regulates Expression of Negative Costimulatory Molecules and Transcriptional Repressors in HIV-1 Primed T cellsManuscript (preprint) (Other academic)
    Abstract [en]

    HIV-1 infection enhances the expression of negative costimulatory molecules on T cellsleading to T cell impairment. The signaling pathway underlying the regulation ofinhibitory molecules and the subsequent onset of T cell impairment remains to beinvestigated. Herein, we showed that the T cells activated by HIV-pulsed dendritic cells(DCs) upregulated CTLA-4, TRAIL, LAG-3, TIM-3, and CD160 and suppressionassociated transcription factors BLIMP-1, DTX1, and FOXP3, leading to T cellsuppression. The induction of suppressor T cells was regulated by the signal transducerand activator of transcription 3 (STAT3) molecules as blockade of this pathwaysignificantly down regulates the expression of inhibitory molecules. The cytokines IL-6and IL-10 were not responsible for STAT3 activation as their neutralization could neitherrecover T cell proliferation nor decrease the expression of negative costimulatorymolecules. Contrarily, we demonstrated that the intracytoplasmic cross-talk of P38Mitogen-Activated Protein Kinase (MAPK) with STAT3 was responsible as blockade ofthe P38MAPK significantly impaired negative costimulatory molecular expression andthe subsequent recovery of T cell proliferation. Notably, the blockade of viral access toDC cytosol, via CD4 binding and fusion, significantly reduced the negative effects DCsimposed on the primed T cells. In conclusion, viral access to cytosol modulated theDCs- T cell priming to induce T cells with upreguled expression of negativecostimulatory molecules in a P38MAPK/STAT3 pathway dependent fashion

  • 8.
    Che, Karlhans Fru
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Shankar, Esaki Muthu
    University of Malaya, Malaysia .
    Muthu, Sundaram
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Messmer, Davorka
    University of California, San Diego, United States.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    p38 Mitogen-Activated Protein Kinase/Signal Transducer and Activator of Transcription-3 Pathway Signaling Regulates Expression of Inhibitory Molecules in T Cells Activated by HIV-1-Exposed Dendritic Cells2012In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 18, no 8, p. 1169-1182Article in journal (Refereed)
    Abstract [en]

    Human immunodeficiency virus type 1 (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 remain elusive. We showed that both autologous and allogeneic T cells exposed to HIV-pulsed dendritic cells (DCs) upregulated cytotoxic T-lymphocyte antigen (CTLA-4), tumor-necrosis factor (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 protein (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, because their blockade significantly abrogated expression of all the inhibitory molecules studied and a subsequent recovery in T-cell proliferation. Neither interleukin-6 (IL-6) nor IL-10 nor growth factors known to activate STAT3 signaling events were responsible for STAT3 activation. Involvement of the P38MAPK/STAT3 pathways was evident because 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 the P38MAPK/STAT3 pathway in T cells, which was responsible for the upregulation of inhibitory molecules. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00103

  • 9. Dias, Sheila
    et al.
    Månsson, Robert
    Gurbuxani, Sandeep
    Sigvardsson, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology .
    Kee, Barbara L.
    E2A Proteins Promote Development of Lymphoid-Primed Multipotent Progenitors2008In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 29, no 2, p. 217-227Article in journal (Refereed)
    Abstract [en]

    The first lymphoid-restricted progeny of hematopoietic stem cells (HSCs) are lymphoid-primed multipotent progenitors (LMPPs), which have little erythromyeloid potential but retain lymphoid, granulocyte, and macrophage differentiation capacity. Despite recent advances in the identification of LMPPs, the transcription factors essential for their generation remain to be identified. Here, we demonstrated that the E2A transcription factors were required for proper development of LMPPs. Within HSCs and LMPPs, E2A proteins primed expression of a subset of lymphoid-associated genes and prevented expression of genes that are not normally prevalent in these cells, including HSC-associated and nonlymphoid genes. E2A proteins also restricted proliferation of HSCs, MPPs, and LMPPs and antagonized differentiation of LMPPs toward the myeloid fate. Our results reveal that E2A proteins play a critical role in supporting lymphoid specification from HSCs and that the reduced generation of LMPPs underlies the severe lymphocyte deficiencies observed in E2A-deficient mice. © 2008 Elsevier Inc. All rights reserved.

  • 10.
    Engström, Linda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ruud, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Eskilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Larsson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mackerlova, Ludmila
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kugelberg, Unn
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Qian, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Vasilache, Ana Maria
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Larsson, Peter
    Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lipopolysaccharide-Induced Fever Depends on Prostaglandin E2 Production Specifically in Brain Endothelial Cells2012In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 153, no 10, p. 4849-4861Article in journal (Refereed)
    Abstract [en]

    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.

  • 11.
    Ericsson, Anna
    et al.
    Lund University.
    Kotarsky, Knut
    Lund University.
    Svensson, Marcus
    Lund University.
    Sigvardsson, Mikael
    Lund University.
    Agace, William
    Lund University.
    Functional characterization of the CCL25 promoter in small intestinal epithelial cells suggests a regulatory role for caudal-related homeobox (Cdx) transcription factors2006In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 176, no 6, p. 3642-3651Article in journal (Refereed)
    Abstract [en]

    The chemokine CCL25 is selectively and constitutively expressed in the small intestinal epithelium and plays an important role in mediating lymphocyte recruitment to this site. In this study, we demonstrate that CCL25 expression in murine small intestinal epithelial cells is independent of signaling through the lymphotoxin 0 receptor and is not enhanced by inflammatory stimuli, pathways involved in driving the expression of most other chemokines. We define a transcriptional start site in the CCL25 gene and a region -141 to -5 proximal of exon 1 that is required for minimal promoter activity in the small intestinal epithelial cell lines, MODE-K and mICc12. These cell lines expressed far less CCL25 mRNA than freshly isolated small intestinal epithelial cells indicating that they are missing important factors driving CCL25 expression. The CCL25 promoter contained putative binding sites for,the intestinal epithelial-associated Caudal-related homeobox (Cdx) transcription factors Cdx-1 and Cdx-2, and small intestinal epithelial cells but not MODE-K and mICc12 cells expressed Cdx-1 and Cdx-2. EMSA analysis demonstrated that Cdx proteins were present in nuclear extracts from freshly isolated small intestinal epithelial cells but not in MODE-K or mICcl2 cells, and bound to putative Cdx sites within the CCL25 promoter. Finally, cotransfection of MODE-K cells with Cdx transcription factors significantly increased CCL25 promoter activity as well as endogenous CCL25 mRNA levels. Together these results demonstrate a unique pattern of regulation for CCL25 and suggest a role for Cdx proteins in regulating CCL25 transcription.

  • 12. Hansson, Frida
    et al.
    Toporski, Jacek
    Månsson, Robert
    Johansson, Bertil
    Norén-Nyström, Ulrika
    Jacobsen, Sten Eirik W
    Wiebe, Thomas
    Larsson, Marcus
    Sigvardsson, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology .
    Castor, Anders
    Exit of pediatric pre-B acute lymphoblastic leukaemia cells from the bone marrow to the peripheral blood is not associated with cell maturation or alterations in gene expression2008In: Molecular Cancer, ISSN 1476-4598, E-ISSN 1476-4598, Vol. 7Article in journal (Refereed)
    Abstract [en]

    Background: Childhood pre-B acute lymphoblastic leukemia (ALL) is a bone marrow (BM) derived disease, which often disseminates out of the BM cavity, where malignant cells to a variable degree can be found circulating in the peripheral blood (PB). Normal pre-B cells are absolutely dependent on BM stroma for survival and differentiation. It is not known whether transformed pre-B ALL cells retain any of this dependence, which possibly could impact on drug sensitivity or MRD measurements. Results: Pre-B ALL cells, highly purified by a novel method using surface expression of CD19 and immunoglobulin light chains, from BM and PB show a very high degree of similarity in gene expression patterns, with differential expression of vascular endothelial growth factor (VEGF) as a notable exception. In addition, the cell sorting procedure revealed that in 2 out of five investigated patients, a significant fraction of the malignant cells had matured beyond the pre-B cell stage. Conclusion: The transition of ALL cells from the BM into the circulation does not demand, or result in, major changes of gene expression pattern. This might indicate an independence of BM stroma on the part of transformed pre-B cells, which contrasts with that of their normal counterparts. © 2008 Hansson et al, licensee BioMed Central Ltd.

  • 13.
    Holm, Pontus C.
    et al.
    Institute for Stem Cell Research, National Research Center for Environment and Health, Neuherberg/Munich.
    Mader, Michael T.
    Institute for Stem Cell Research, National Research Center for Environment and Health, Neuherberg/Munich.
    Haubst, Nicole
    Institute for Stem Cell Research, National Research Center for Environment and Health, Neuherberg/Munich.
    Wizenmann, Andrea
    Institute for Stem Cell Research, National Research Center for Environment and Health, Neuherberg/Munich.
    Sigvardsson, Mikael
    Lund University.
    Goetz, Magdalena
    Institute for Stem Cell Research, National Research Center for Environment and Health, Neuherberg/Munich.
    Loss- and gain-of-function analyses reveal targets of Pax6 in the developing mouse telencephalon2007In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 34, no 1, p. 99-119Article, review/survey (Refereed)
    Abstract [en]

    Appropriate neurogenesis and patterning of the forebrain requires the transcription factor Pax6, yet it is largely unknown how Pax6 exerts its effects at the molecular level. To characterize Pax6-mediated regulation of gene expression during murine forebrain neurogenesis, we performed microarray analysis with tissue from the dorsal Pax6-dependent telencephalon and the ventral Pax6-negative telencephalon at the onset of neurogenesis (E12) and at mid-neurogenesis (E15) in wild-type and Pax6-deficient mutant littermates. In the Pax6-deficient cortex the expression levels of various transcription factors involved in neurogenesis (like Satb2, Nfia, AP-2 gamma, NeuroD6, Ngn2, Tbr2, Bhlhb5) and the retinoic acid signalling molecule Rlbp1 were reduced. Regulation by Pax6 could be confirmed upon electroporation of a Pax6- and a dominant-negative Pax6-containing vector into embryonic cortex. Taken together, our data reveal novel insights into the molecular pathways regulated by Pax6 during cortical neurogenesis. Most intriguingly, this analysis revealed time- and region-specific differences in Pax6-mediated transcription, explaining the specific function of Pax6 at early and later stages of neurogenesis.

  • 14.
    I Siponen, Marina
    et al.
    Karolinska Institute.
    Wisniewska, Magdalena
    Karolinska Institute.
    Lehtio, Lari
    Abo Akademy University.
    Johansson, Ida
    Karolinska Institute.
    Svensson, Linda
    Karolinska Institute.
    Raszewski, Grzegorz
    Karolinska Institute.
    Nilsson, Lennart
    Karolinska Institute.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Berglund, Helena
    Karolinska Institutet.
    Structural Determination of Functional Domains in Early B-cell Factor (EBF) Family of Transcription Factors Reveals Similarities to Rel DNA-binding Proteins and a Novel Dimerization Motif2010In: JOURNAL OF BIOLOGICAL CHEMISTRY, ISSN 0021-9258, Vol. 285, no 34, p. 25875-25879Article in journal (Refereed)
    Abstract [en]

    The early B-cell factor (EBF) transcription factors are central regulators of development in several organs and tissues. This protein family shows low sequence similarity to other protein families, which is why structural information for the functional domains of these proteins is crucial to understand their biochemical features. We have used a modular approach to determine the crystal structures of the structured domains in the EBF family. The DNA binding domain reveals a striking resemblance to the DNA binding domains of the Rel homology superfamily of transcription factors but contains a unique zinc binding structure, termed zinc knuckle. Further the EBF proteins contain an IPT/TIG domain and an atypical helix-loop-helix domain with a novel type of dimerization motif. The data presented here provide insights into unique structural features of the EBF proteins and open possibilities for detailed molecular investigations of this important transcription factor family.

  • 15.
    Jensen, Christina T.
    et al.
    Lund University.
    Böiers, Charlotta
    Lund University.
    Kharazi, Shabnam
    Lund University.
    Lübking, Anna
    Lund University.
    Rydén, Tobias
    Lund University.
    Sigvardsson, Mikael
    Lund University.
    Sitnicka, Ewa
    Lund University.
    Jacobsen, Sten Eirik W.
    Lund University.
    Permissive roles of hematopoietin and cytokine tyrosine kinase receptors in early T-cell development2008In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 111, no 4, p. 2083-2090Article in journal (Refereed)
    Abstract [en]

    Although several cytokines have been demonstrated to be critical regulators of development of multiple blood cell lineages, it remains disputed to what degree they act through instructive or permissive mechanisms. Signaling through the FMS-like tyrosine kinase 3 (FLT3) receptor and the hematopoietin IL-7 receptor alpha (IL-7Ralpha) has been demonstrated to be of critical importance for sustained thymopoiesis. Signaling triggered by IL-7 and thymic stromal lymphopoietin (TSLP) is dependent on IL-7Ralpha, and both ligands have been implicated in T-cell development. However, we demonstrate that, whereas thymopoiesis is abolished in adult mice doubly deficient in IL-7 and FLT3 ligand (FLT3L), TSLP does not play a key role in IL-7-independent or FLT3L-independent T lymphopoiesis. Furthermore, whereas previous studies implicated that the role of other cytokine tyrosine kinase receptors in T lymphopoiesis might not involve permissive actions, we demonstrate that ectopic expression of BCL2 is sufficient not only to partially correct the T-cell phenotype of Flt3l(-/-) mice but also to rescue the virtually complete loss of all discernable stages of early T lymphopoiesis in Flt3l(-/-)Il7r(-/-) mice. These findings implicate a permissive role of cytokine receptors of the hematopoietin and tyrosine kinase families in early T lymphopoiesis. 

  • 16.
    Jimenez, Maria A
    et al.
    Beth Israel Deaconess Medical Center, Boston.
    Åkerblad, Peter
    Astra Zeneca R&D.
    Sigvardsson, Mikael
    Lund University.
    Rosen, Evan D
    Beth Israel Deaconess Medical Center, Boston.
    Critical role for Ebf1 and Ebf2 in the adipogenic transcriptional cascade2007In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 27, no 2, p. 743-757Article in journal (Refereed)
    Abstract [en]

    The Ebf (O/E) family of helix-loop-helix transcription factors plays a significant role in B lymphocyte and neuronal development. The three primary members of this family, Ebf1, 2, and 3, are all expressed in adipocytes, and Ebf1 promotes adipogenesis when overexpressed in NIH 3T3 fibroblasts. Here we report that these three proteins have adipogenic potential in multiple cellular models and that peroxisome proliferator-activated receptor (PPAR) is required for this effect, at least in part due to direct activation of the PPAR1 promoter by Ebf1. Ebf1 also directly binds to and activates the C/EBP promoter, which exerts positive feedback on C/EBP expression. Despite this, C/EBP is dispensable for the adipogenic action of Ebf proteins. Ebf1 itself is induced by C/EBPß and , which bind and activate its promoter. Reduction of Ebf1 and Ebf2 proteins by specific short hairpin RNA blocks differentiation of 3T3-L1 cells, suggesting a critical role for these factors and the absence of functional redundancy between members of this family. Altogether, these data place Ebf1 within the known transcriptional cascade of adipogenesis and suggest critical roles for Ebf1 and Ebf2.

  • 17.
    Kranc, Kamil R.
    et al.
    University of Oxford, UK.
    Schepers, Hein
    University of Oxford, UK.
    Rodrigues, Neil P.
    University of Oxford, UK.
    Bamforth, Simon
    Newcastle University, UK.
    Villadsen, Ellen
    University of Oxford, UK.
    Ferry, Helen
    University of Oxford, UK.
    Bouriez-Jones, Tiphaine
    University of Oxford, UK.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Bhattacharya, Shoumo
    University of Oxford, UK.
    Jacobsen, Sten Eirik
    University of Oxford, UK.
    Enver, Tariq
    University of Oxford, UK.
    Cited2 Is an Essential Regulator of Adult Hematopoietic Stem Cells2009In: Cell Stem Cell, ISSN 1934-5909, Vol. 5, no 6, p. 659-665Article in journal (Refereed)
    Abstract [en]

    The regulatory pathways necessary for the maintenance of adult hematopoietic stem cells (HSCs) remain poorly defined. By using loss-of-function approaches, we report a selective and cell-autonomous requirement for the p300/CBP-binding transcriptional coactivator Cited2 in adult HSC maintenance. Conditional deletion of Cited2 in the adult mouse results in loss of HSCs causing multilineage bone marrow failure and increased lethality. In contrast, conditional ablation of Cited2 after lineage specification in lymphoid and myeloid lineages has no impact on the maintenance of these lineages. Additional deletion of Ink4a/Arf (encoding p16Ink4a and p19Arf) or Trp53 (encoding p53, a downstream target of p19Arf) in a Cited2-deficient background restores HSC functionality and rescues mice from bone marrow failure. Furthermore, we show that the critical role of Cited2 in primitive hematopoietic cells is conserved in humans. Taken together, our studies provide genetic evidence that Cited2 selectively maintains adult HSC functions, at least in part, via Ink4a/Arf and Trp53.

  • 18.
    Lagergren, A
    et al.
    Lund University.
    Manetopoulos, C
    Lund University.
    Axelson, H
    Lund University.
    Sigvardsson, Mikael
    Lund University.
    Neuroblastoma and pre-B lymphoma cells share expression of key transcription factors but display tissue restricted target gene expression2004In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 4, no 80Article in journal (Refereed)
    Abstract [en]

    Background: Transcription factors are frequently involved in the process of cellular transformation, and many malignancies are characterized by a distinct genetic event affecting a specific transcription factor. This probably reflects a tissue specific ability of transcription factors to contribute to the generation of cancer but very little is known about the precise mechanisms that governs these restricted effects. Methods: To investigate this selectivity in target gene activation we compared the overall gene expression patterns by micro-array analysis and expression of target genes for the transcription factor EBF in lymphoma and neuroblastoma cells by RT-PCR. The presence of transcription factors in the different model cell lines was further investigated by EMSA analysis. Results: In pre-B cells mb-1 and CD19 are regulate by EBF-1 in collaboration with Pax-5 and E-proteins. We here show that neuroblastoma cells express these three, for B cell development crucial transcription factors, but nevertheless fail to express detectable levels of their known target genes. Expression of mb-1 could, however, be induced in neuroblastoma cells after disruption of the chromatin structure by treatment with 5-azacytidine and Trichostatin A. Conclusion: These data suggest that transcription factors are able to selectively activate target genes in different tissues and that chromatin structure plays a key role in the regulation of this activity.

  • 19.
    Lagergren, Anna
    et al.
    Department for Hematopoetic Stem Cell Biology, Lund Stemcell Center, Lund University, Lund, Sweden.
    Månsson, Robert
    Department for Hematopoetic Stem Cell Biology, Lund Stemcell Center, Lund University, Lund, Sweden.
    Zetterblad, Jenny
    Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
    Smith, Emma
    Department for Hematopoetic Stem Cell Biology, Lund Stemcell Center, Lund University, Lund, Sweden.
    Basta, Barbro
    Department of Molecular Pharmacology, AstraZeneca R&D Mölndal, Sweden.
    Bryder, David
    Department for Hematopoetic Stem Cell Biology, Lund Stemcell Center, Lund University, Lund, Sweden.
    Åkerblad, Peter
    Department of Molecular Pharmacology, AstraZeneca R&D Mölndal, Sweden.
    Sigvardsson, Mikael
    Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
    The Cxcl12, Periostin, and Ccl9 genes are direct targets for early B-cell factor in OP-9 stroma cells2007In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 282, no 19, p. 14454-14462Article in journal (Refereed)
    Abstract [en]

    The development of blood cells from hematopoietic stem cells in the bone marrow is dependent on communication with bone marrow stroma cells, making these cells central for the appropriate regulation of hematopoiesis. To identify transcription factors that may play a role in gene regulation in stroma cells, we performed comparative gene expression analysis of fibroblastic NIH3T3 cells, unable to support hematopoiesis in vitro, and OP-9 stroma cells, highly efficient in this regard. These experiments revealed that transcription factors of the early B cell factor (EBF) family were highly expressed in OP-9 cells as compared with the NIH3T3 cells. To identify potential targets genes for EBF proteins in stroma cells, we overexpressed EBF in fibroblasts and analyzed the pattern of induced genes by microarray analysis. This revealed that EBF was able to up-regulate expression of among others the Cxcl12, Ccl9, and Periostin genes. The identification of relevant promoters revealed that they all contained functional EBF binding sites able to interact with EBF in OP-9 cells. Furthermore, ectopic expression of a dominant negative EBF protein or antisense EBF-1 RNA in OP-9 stroma cells resulted in reduced expression of these target genes. These data suggest that EBF proteins might have dual roles in hematopoiesis acting both as intrinsic regulators of B-lymphopoiesis and as regulators of genes in bone marrow stroma cells. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

  • 20. Lietz, Andreas
    et al.
    Janz, Martin
    Sigvardsson, Mikael
    Lund University.
    Jundt, Franziska
    Dörken, Bernd
    Mathas, Stephan
    Loss of bHLH transcription factor E2A activity in primary effusion lymphoma confers resistance to apoptosis2007In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 137, no 4, p. 342-348Article in journal (Refereed)
    Abstract [en]

    Similar to classical Hodgkin lymphoma (HL) tumour cells, primary effusion lymphoma (PEL) originates from mature B cells but displays a non-B cell phenotype, the mechanisms and consequences of which are not yet understood. This study showed that PEL lacked DNA binding activity of the B cell-determining transcription factors E2A, EBF and Pax5. PEL overexpressed the E2A antagonists ABF-1 and Id2, which have been described to block the B-cell differentiation program in classical HL. However, in contrast to HL cells, B lineage-inappropriate genes were not similarly upregulated in PEL, and reconstitution of B cell-specific E2A homodimer activity in PEL induced apoptosis. These data demonstrate that lineage infidelity in PEL is not as pronounced as in HL, and that the loss of the B cell-specific transcription factor E2A in PEL is implicated in apoptosis protection.

  • 21.
    Lukin, Kara
    et al.
    National Jewish Health.
    Fields, Scott
    National Jewish Health.
    Guerrettaz, Lisa
    National Jewish Health.
    Straign, Desiree
    National Jewish Health.
    Rodriguez, Valerie
    National Jewish Health.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Mansson, Robert
    Lund Strategic Centre for Stem Cell Biology.
    Cambier, John C.
    National Jewish Health.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Hagman, James
    National Jewish Health.
    A dose-dependent role for EBF1 in repressing non-B-cell-specific genes2011In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 41, no 6, p. 1787-1793Article in journal (Refereed)
    Abstract [en]

    In the absence of early B-cell factor 1 (EBF1), B-cell development is arrested at an uncommitted progenitor stage that exhibits increased lineage potentials. Previously, we investigated the roles of EBF1 and its DNA-binding partner Runx1 by evaluating B lymphopoiesis in single (EBF1(het) and Runx1(het)) and compound haploinsufficent (Ebf1(+/-) Runx1(+/-), ER(het)) mice. Here, we demonstrate that decreased Ebf1 gene dosage results in the inappropriate expression of NK-cell lineage-specific genes in B-cell progenitors. Moreover, prolonged expression of Ly6a/Sca-1 suggested the maintenance of a relatively undifferentiated phenotype. These effects were exacerbated by reduced expression of Runx1 and occurred despite expression of Pax5. Repression of inappropriately expressed genes was restored in most pre-B and all immature B cells of ER(het) mice. Enforced EBF1 expression repressed promiscuous transcription in pro-B cells of ER(het) mice and in Ebf1(-/-) Pax5(-/-) fetal liver cells. Together, our studies suggest that normal levels of EBF1 are critical for maintaining B-cell identity by directing repression of non-B-cell-specific genes.

  • 22.
    Löfstedt, T
    et al.
    Lund University.
    Jögi, A
    Lund University.
    Sigvardsson, Mikael
    Lund University.
    Gradin, K
    Karolinska Institute.
    Poellinger, L
    Karolinska Institute.
    Påhlman, S
    Lund University.
    Axelson, H
    Lund University.
    Induction of ID2 expression by hypoxia-inducible factor-1 - A role in dedifferentiation of hypoxic neuroblastoma cells2004In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 279, no 38, p. 39223-39231Article in journal (Refereed)
    Abstract [en]

    ID ( inhibitor of differentiation/DNA binding) proteins, frequently deregulated in advanced human malignancies, can participate in multiple fundamental traits of cancer, such as block of differentiation, increased proliferation, tissue invasiveness, and angiogenesis. We have previously demonstrated that hypoxia decreases expression of neuronal marker genes in neuroblastoma, but induces genes expressed in the neural crest, such as ID2. Because of its involvement in normal neural crest development and its ability to inhibit proneuronal bHLH proteins, the hypoxic induction of ID2 was of particular interest. Here we report fast induction kinetics of ID2 expression in hypoxic neuroblastoma cells. The up-regulation of ID2 was abolished by addition of actinomycin D, implicating a hypoxia-driven transcriptional mechanism. Analyzing the ID2 promoter revealed several potential binding sites for hypoxia-inducible factors. Subsequent electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated two functional HIF-1 binding sites within ID2 gene regulatory sequences located at -725 and -1893 relative to the transcriptional initiation point. In transfection assays, DNA constructs of the ID2 promoter, including the functional HIF-1 binding sites, induced luciferase reporter activity in a HIF-1-specific manner. These observations demonstrate that ID2 is actively engaged by hypoxia and represents a novel HIF-1 target. Hypoxia-induced ID2 expression could play a significant role in the previously observed dedifferentiation of hypoxic neuroblastoma cells, which in a clinical setting could lead to less mature and more aggressive tumors.

  • 23.
    Magnusson, Mattias
    et al.
    Lund University Hospital.
    Brun, Ann CM
    Lund University Hospital.
    Miyake, Noriko
    Lund University Hospital.
    Larsson, Jonas
    Lund University Hospital.
    Ehinger, Mats
    Lund University Hospital.
    Bjornsson, Jon Mar
    Lund University Hospital.
    Wutz, Anton
    Whitehead Institute for Biomedical Research.
    Sigvardsson, Mikael
    Lund University Hospital.
    Karlsson, Stefan
    Lund University Hospital.
    HOXA10 is a critical regulator for hematopoietic stem cells and erythroid/megakaryocyte development2007In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 109, no 9, p. 3687-3696Article in journal (Refereed)
    Abstract [en]

    The Homeobox (Hox) transcription factors are important regulators of normal and malignant hematopoiesis because they control proliferation, differentiation, and self-renewal of hematopoietic cells at different levels of the hematopoietic hierarchy. In transgenic mice we show that the expression of HOXA10 is tightly regulated by doxycycline. Intermediate concentrations of HOXA10 induced a 15-fold increase in the repopulating capacity of hematopoietic stem cells (HSCs) after 13 days of in vitro culture. Notably, the proliferation induction of HSC by HOXA10 was dependent on the HOXA10 concentration, because high levels of HOXA10 had no effect on HSC proliferation. Furthermore, high levels of HOXA10 blocked erythroid and megakaryocyte development, demonstrating that tight regulation of HOXA10 is critical for normal development of the erythroid and megakaryocytic lineages. The HOXA10-mediated effects on hematopoietic cells were associated with altered expression of genes that govern stem-cell self-renewal and lineage commitment (eg, hepatic leukemia factor [HlF], Dickkopf-1 [Dkk-1], growth factor independent-1 [Gfi-1], and Gata-1). Interestingly, binding sites for HOXA10 were found in HLF, Dkk-1, and Gata-1, and Dkk-1 and Gfi-1 were transcriptionally activated by HOXA10. These findings reveal novel molecular pathways that act downstream of HOXA10 and identify HOXA10 as a master regulator of postnatal hematopoietic development.

  • 24.
    Man Wong, Wan
    et al.
    Lund University, Sweden .
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Astrand-Grundstrom, Ingbritt
    Lund University, Sweden .
    Hogge, Donna
    BC Cancer Agency, Canada .
    Larsson, Jonas
    Lund University, Sweden .
    Qian, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Ekblom, Marja
    Lund University, Sweden .
    Expression of Integrin alpha 2 Receptor in Human Cord Blood CD34+CD38-CD90+Stem Cells Engrafting Long-Term in NOD/SCID-IL2R gamma(c)null Mice2013In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 31, no 2, p. 360-371Article in journal (Refereed)
    Abstract [en]

    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-IL2R gamma(c)null (NSG) mice long-term, at 24 weeks after transplantation, can be prospectively isolated at an increased purity by using integrin alpha 2 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 alpha 2 receptor, with a frequency of 1/29 cells, as compared to a frequency of 1/157 in the corresponding integrin alpha 2- cells. In line with this, long-term reconstituting stem cells within the cord blood CD34+CD38- cell population were significantly enriched in the integrin alpha 2+ fraction, while stem cells and progenitors reconstituting short-term, at 8-12 weeks, were heterogeneous in integrin alpha 2 expression. Global gene expression profiling revealed that the lineage-marker negative (Lin-) CD34+CD38-CD90+CD45RA- integrin alpha 2+ cell population was molecularly distinct from the integrin alpha 2- cell population and the more mature Lin-CD34+CD38-CD90-CD45RA- cell population. Our findings identify integrin alpha 2 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 2013;31:360-371

  • 25.
    Mansson, R.
    et al.
    Månsson, R., Department for Hematopoetic Stem Cell Biology, Lund Stemcell Center, Lund University, S-221 84 Lund, Sweden.
    Lagergren, A.
    Department for Hematopoetic Stem Cell Biology, Lund Stemcell Center, Lund University, S-221 84 Lund, Sweden.
    Hansson, F.
    Department for Hematopoetic Stem Cell Biology, Lund Stemcell Center, Lund University, S-221 84 Lund, Sweden.
    Smith, E.
    Department for Hematopoetic Stem Cell Biology, Lund Stemcell Center, Lund University, S-221 84 Lund, Sweden.
    Sigvardsson, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology .
    The CD53 and CEACAM-1 genes are genetic targets for early B cell factor2007In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 37, no 5, p. 1365-1376Article in journal (Refereed)
    Abstract [en]

    Early B cell factor (EBF)-1 is a transcription factor known to be of critical importance for early B lymphocyte development. EBF-1 has been shown to directly interact with and regulate expression of a set of genes involved in the functional formation of the pre-B cell receptor, but the dramatic phenotype observed in the EBF-1-deficient mice suggests that several additional genes are activated by this protein. In order to identify additional target genes for EBF-1, we transduced a hematopoietic progenitor cell line, BaF/3, with an EBF-1-encoding retrovirus and investigated the induced gene expression pattern by micro-arrays. This analysis suggested that among others, the CD53 and the carcinoembryonic antigen-related cell adhesion molecule (CEAACAM)-1 genes both were induced by ectopic expression of EBF-1. Identification of the 5' end of the cDNA enabled the identification of promoter elements with functional binding sites for EBF-1 and ability to respond to EBF-1 expression in transient transfection assays. These data suggest that CD53 and CEACAM-1 are direct genetic targets for EBF-1, providing additional information concerning the activity of this crucial transcription factor in hematopoiesis. © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  • 26.
    Mansson, R
    et al.
    Lund University.
    Tsapogas, P
    Lund University.
    Akerlund, M
    Lund University.
    Lagergren, A
    Lund University.
    Gisler, R
    Lund University.
    Sigvardsson, Mikael
    Lund University.
    Pearson correlation analysis of microarray data allows for the identification of genetic targets for early B-cell factor2004In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 279, no 17, p. 17905-17913Article in journal (Refereed)
    Abstract [en]

    B lymphocyte development is a complex biological process critically dependent on the transcription factor early B cell factor (EBF). To deepen understanding of the roles for EBF in this process, we have used Pearson correlation analysis to evaluate microarray data from a set of mouse B lymphoid cell lines representing different stages of development. Comparing the expression pattern of EBF to that of the other genes in the data set revealed that VpreB1, mb-1, and lambda5, all known target genes, presented high correlation values to EBF. High correlations were also seen for the VpreB3 and CD19 genes and biochemical as well as functional data supported that they are target genes for EBF even though the expression of CD19 was critically dependent of Pax-5. We also obtained evidence for extensive collaborative actions of EBF and E47 even though microarray analysis of hematopoetic progenitor cells ectopically expressing these proteins suggested that they activated only a subset of pre-B cell restricted genes.

  • 27.
    Mansson, Robert
    et al.
    University of California, San Diego, USA .
    Welinder, Eva
    University of California, San Diego, USA .
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Lin, Yin C.
    University of California, San Diego, USA .
    Benner, Christopher
    University of California, San Diego, USA .
    Glass, Christopher K.
    University of California, San Diego, USA .
    Lucas, Joseph S.
    University of California, San Diego, USA .
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Murre, Cornelis
    University of California, San Diego, USA .
    Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 51, p. 21028-21033Article in journal (Refereed)
    Abstract [en]

    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.

  • 28.
    Mathas, S
    et al.
    Max-Delbrück-Center for Molecular Medicine, Berlin.
    Janz, M
    Max-Delbrück-Center for Molecular Medicine, Berlin.
    Hummel, F
    Medical University Berlin.
    Hummel, M
    Medical University Berlin.
    Wollert-Wulf, B
    Medical University Berlin.
    Lusatis, S
    Medical University Berlin.
    Anagnostopoulos, I
    Medical University Berlin.
    Lietz, A
    Medical University Berlin.
    Sigvardsson, Mikael
    Lund University.
    Jundt, F
    Max-Delbrück-Center for Molecular Medicine, Berlin.
    Jöhrens, K
    Medical University Berlin.
    Bommert, K
    Medical University Berlin.
    Stein, H
    Medical University Berlin.
    Dorken, B
    Max-Delbrück-Center for Molecular Medicine, Berlin.
    Intrinsic inhibition of transcription factor E2A by HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma2006In: Nature Immunology, ISSN 1529-2908, E-ISSN 1529-2916, Vol. 7, no 2, p. 207-215Article in journal (Refereed)
    Abstract [en]

    B cell differentiation is controlled by a complex network of lineage-restricted transcription factors. How perturbations to this network alter B cell fate remains poorly understood. Here we show that classical Hodgkin lymphoma tumor cells, which originate from mature B cells, have lost the B cell phenotype as a result of aberrant expression of transcriptional regulators. The B cell-specific transcription factor program was disrupted by overexpression of the helix-loop-helix proteins ABF-1 and Id2. Both factors antagonized the function of the B cell-determining transcription factor E2A. As a result, expression of genes specific to B cells was lost and expression of genes not normally associated with the B lineage was upregulated. These data demonstrate the plasticity of mature human lymphoid cells and offer an explanation for the unique classical Hodgkin lymphoma phenotype.

  • 29.
    Mercer, Elinore M
    et al.
    University of California San Diego.
    Lin, Yin C
    University of California San Diego.
    Benner, Christopher
    University of California San Diego.
    Jhunjhunwala, Suchit
    University of California San Diego.
    Dutkowski, Janusz
    University of California San Diego.
    Flores, Martha
    University of California San Diego.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Ideker, Trey
    University of California San Diego.
    Glass, Christopher K
    University of California San Diego.
    Murre, Cornelis
    University of California San Diego.
    Multilineage Priming of Enhancer Repertoires Precedes Commitment to the B and Myeloid Cell Lineages in Hematopoietic Progenitors2011In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 35, no 3, p. 413-425Article in journal (Refereed)
    Abstract [en]

    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.

  • 30.
    Merluzzi, S
    et al.
    University of Udine, Italy.
    Moretti, M
    University of Udine, Italy.
    Altamura, S
    University of Udine, Italy.
    Zwollo, P
    The College of William and Mary, Williamsburg, Virginia .
    Sigvardsson, Mikael
    Lund University.
    Vitale, G
    University of Udine, Italy.
    Pucillo, C
    University of Udine, Italy.
    CD40 stimulation induces Pax5/BSAP and EBF activation through a APE/ref-1-dependent redox mechanism2004In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 279, no 3, p. 1777-1786Article in journal (Refereed)
    Abstract [en]

    CD40 is a member of the growing tumor necrosis factor receptor family that has been shown to play important roles in T cell-mediated B lymphocyte activation. Ligation of B cell CD40 by CD154, mainly expressed on activated T cells, stimulates B cell proliferation, differentiation, isotype switching, up-regulation of surface molecules contributing to antigen presentation, development of the germinal center, and the humoral memory response. In this study we demonstrate that the redox factor APE/Ref-1 acts as a key signaling intermediate in response to CD40-mediated B cell activation. The transcription factors Pax5a or BSAP ( B cell lineage-specific activator protein) and EBF ( early B cell factor) are constitutively expressed in spleen B cells and CD40 cross-linking induces increases in Pax5a and EBF binding activity compared with nonstimulated B cells. We show that upon CD40 antibody-mediated cross-linking, APE/Ref-1 translocates from the cytoplasm to the nucleus of activated B cells, where it modulates the DNA binding activity of both Pax5a and EBF. Moreover, we show that the repression of APE/Ref-1 protein production is able to block CD40-mediated Pax5a activation. We also provide evidence that APE/Ref-1 can modulate the cooperative activation of the blk promoter operated by Pax5a and EBF and that APE/Ref-1 might directly regulate EBF functional activity. Finally, we show that the interaction between Pax5a and EBF enhances EBF binding activity to its consensus sequence, suggesting that Pax5a can physically interact with EBF and modulate its DNA binding activity.

  • 31.
    Månsson, Robert
    et al.
    Lund University.
    Hultquist, Anne
    Lund University.
    Luc, Sidinh
    Lund University.
    Yang, Liping
    Lund University.
    Anderson, Kristina
    Lund University.
    Kharazi, Shabnam
    Lund University.
    Al-Hashmi, Suleiman
    Lund University.
    Liuba, Karina
    Lund University.
    Thorén, Lina
    Lund University.
    Adolfsson, Jörgen
    Lund University.
    Buza-Vidas, Natalija
    Lund University.
    Qian, Hong
    Lund University.
    Soneji, Shamit
    University of Oxford.
    Enver, Tariq
    University of Oxford.
    Sigvardsson, Mikael
    Lund University.
    Jacobsen, Sten Eirik W
    Lund University.
    Molecular evidence for hierarchical transcriptional lineage priming in fetal and adult stem cells and multipotent progenitors2007In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 26, no 4, p. 407-419Article in journal (Refereed)
    Abstract [en]

    Recent studies implicated the existence of adult lymphoid-primed multipotent progenitors (LMPPs) with little or no megakaryocyte-erythroid potential, questioning common myeloid and lymphoid progenitors as obligate intermediates in hematopoietic stem cell (HSC) lineage commitment. However, the existence of LMPPs remains contentious. Herein, global and single-cell analyses revealed a hierarchical organization of transcriptional lineage programs, with downregulation of megakaryocyte-erythroid genes from HSCs to LMPPs, sustained granulocyte-monocyte priming, and upregulation of common lymphoid (but not B and T cell-specific) genes. These biological and molecular relationships, implicating almost mutual exclusion of megakaryocyte-erythroid and lymphoid pathways, are established already in fetal hematopoiesis, as evidenced by existence of LMPPs in fetal liver. The identification of LMPPs and hierarchically ordered transcriptional activation and downregulation of distinct lineage programs is compatible with a model for HSC lineage commitment in which the probability for undergoing different lineage commitment fates changes gradually when progressing from HSCs to LMPPs.

  • 32.
    Månsson, Robert
    et al.
    Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Anderson, Kristina
    Hematopoietic Stem Cell Laboratory Lund University, Sweden.
    Mårtensson, Inga-Lill
    Laboratory of Lymphocyte Signaling and Development The Babraham Institute, Cambridge, United Kingdom.
    Jacobsen, Sten Eirik W.
    Hematopoietic Stem Cell Laboratory Lund University.
    Bryder, David
    Department of Immunology Lund University, Sweden.
    Sigvardsson, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology .
    B-lineage commitment prior to surface expression of B220 and CD19 on hematopoietic progenitor cells2008In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 112, no 4, p. 1048-1055Article in journal (Refereed)
    Abstract [en]

    Commitment of hematopoietic progenitor cells to B-lymphoid cell fate has been suggested to coincide with the development of PAX5-expressing B220 +CD19+ pro-B cells. We have used a transgenic reporter mouse, expressing human CD25 under the control of the B-lineage- restricted IgII1 (λ5) promoter to investigate the lineage potential of early progenitor cells in the bone marrow. This strategy allowed us to identify a reporter expressing LIN-B220- CD19-CD127 +FLT3+ SCA1lowKITlow population that displays a lack of myeloid and a 90% reduction in in vitro T-cell potential compared with its reporter-negative counterpart. Gene expression analysis demonstrated that these lineage-restricted cells express B- lineage-associated genes to levels comparable with that observed in pro-B cells. These data suggest that B-lineage commitment can occur before the expression of B220 and CD19. © 2008 by The American Society of Hematology.

  • 33.
    Månsson, Robert
    et al.
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Welinder, Eva
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Tsapogas, Panagiotis
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Sakaguchi, Nobuo
    Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
    Bryder, David
    Department for Immunology, Lund University, Lund, Sweden .
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Single-cell analysis of the common lymphoid progenitor compartment reveals functional and molecular heterogeneity2010In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, no 13, p. 2601-2609Article in journal (Refereed)
    Abstract [en]

    To investigate molecular events involved in the regulation of lymphoid lineage commitment, we crossed lambda 5 reporter transgenic mice to Rag1-GFP knockin mice. This allowed us to subfractionate common lymphoid progenitors and pre-pro-B (fraction A) cells into lambda 5(-)Rag1(low), lambda 5(-)Rag1(high), and lambda 5(+)Rag1(high) cells. Clonal in vitro differentiation analysis demonstrated that Rag1(low) cells gave rise to B/T and NK cells. Rag1(high) cells displayed reduced NK-cell potential with preserved capacity to generate B- and T-lineage cells, whereas the lambda 5(+) cells were B-lineage restricted. Ebf1 and Pax5 expression was largely confined to the Rag1high populations. These cells also expressed a higher level of the surface protein LY6D, providing an additional tool for the analysis of early lymphoid development. These data suggest that the classic common lymphoid progenitor compartment composes a mixture of cells with relatively restricted lineage potentials, thus opening new possibilities to investigate early hematopoiesis.

  • 34.
    Nelander, S
    et al.
    Sahlgrenska Academy.
    Larsson, E
    Sahlgrenska Academy.
    Kristiansson, E
    Chalmers Technical University.
    Månsson, R
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy.
    Nerman, O
    Chalmers Technical University.
    Sigvardsson, Mikael
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy.
    Mostad, P
    Chalmers Technical University.
    Lindahl, P
    Sahlgrenska Academy.
    Predictive screening for regulators of conserved functional gene modules (gene batteries) in mammals2005In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 6, no 68Article in journal (Refereed)
    Abstract [en]

    Background: The expression of gene batteries, genomic units of functionally linked genes which are activated by similar sets of cis- and trans-acting regulators, has been proposed as a major determinant of cell specialization in metazoans. We developed a predictive procedure to screen the mouse and human genomes and transcriptomes for cases of gene-battery-like regulation. Results: In a screen that covered andSIM; 40 per cent of all annotated protein-coding genes, we identified 21 co-expressed gene clusters with statistically supported sharing of cis- regulatory sequence elements. 66 predicted cases of over-represented transcription factor binding motifs were validated against the literature and fell into three categories: (i) previously described cases of gene battery-like regulation, (ii) previously unreported cases of gene battery-like regulation with some support in a limited number of genes, and (iii) predicted cases that currently lack experimental support. The novel predictions include for example Sox 17 and RFX transcription factor binding sites that were detected in andSIM; 10% of all testis specific genes, and HNF-1 and 4 binding sites that were detected in andSIM; 30% of all kidney specific genes respectively. The results are publicly available at http://www.wlab.gu.se/lindahl/genebatteries. Conclusion: 21 co-expressed gene clusters were enriched for a total of 66 shared cis-regulatory sequence elements. A majority of these predictions represent novel cases of potential co-regulation of functionally coupled proteins. Critical technical parameters were evaluated, and the results and the methods provide a valuable resource for future experimental design.

  • 35.
    Nilsson, Lars
    et al.
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy.
    Edén, Patrik
    Lund University.
    Olsson, Eleonor
    Lund University.
    Månsson, Robert
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy.
    Åstrand-Grundström, Ingbritt
    Lund University.
    Strömbeck, Bodil
    Lund University.
    Theilgaard-Mönch, Kim
    University of Copenhagen.
    Anderson, Kristina
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy.
    Hast, Robert
    Karolinska University Hospital.
    Hellström-Lindberg, Eva
    Karolinska University Hospital.
    Samuelsson, Jan
    Karolinska Institute.
    Bergh, Gösta
    Helsingborg Hospital.
    Nerlov, Claus
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy.
    Johansson, Bertil
    Lund University.
    Sigvardsson, Mikael
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy.
    Borg, Åke
    Lund University.
    Jacobsen, Sten Eirik W
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy.
    The molecular signature of MDS stem cells supports a stem-cell origin of 5q-myelodysplastic syndromes2007In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 110, no 8, p. 3005-3014Article in journal (Refereed)
    Abstract [en]

    Global gene expression profiling of highly purified 5q-deleted CD34+CD38Thy1+ cells in 5q– myelodysplastic syndromes (MDSs) supported that they might originate from and outcompete normal CD34+CD38Thy1+ hematopoietic stem cells. Few but distinct differences in gene expression distinguished MDS and normal stem cells. Expression of BMI1, encoding a critical regulator of self-renewal, was up-regulated in 5q– stem cells. Whereas multiple previous MDS genetic screens failed to identify altered expression of the gene encoding the myeloid transcription factor CEBPA, stage-specific and extensive down-regulation of CEBPA was specifically observed in MDS progenitors. These studies establish the importance of molecular characterization of distinct stages of cancer stem and progenitor cells to enhance the resolution of stage-specific dysregulated gene expression.

  • 36.
    Nilsson-Berglund, Lisa M
    et al.
    Department of Clinical Sciences in Malmö, Lund University, Malmö.
    Zetterqvist, Anna V.
    Department of Clinical Sciences in Malmö, Lund University, Malmö.
    Nilsson-Öhman, Jenny
    Department of Clinical Sciences in Malmö, Lund University, Malmö.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Gonzalez Bosc, Laura V
    Department of Cell Biology & Physiology, School of Medicine, University of New Mexico, Albuquerque, New Mexico, USA.
    Smith, Maj-Lis
    Department of Clinical Sciences in Malmö, Lund University, Malmö.
    Salehi, Albert
    Department of Clinical Sciences in Malmö, Lund University, Malmö.
    Agardh, Elisabet
    Department of Clinical Sciences in Malmö, Lund University, Malmö.
    Nordin Fredrikson, Gunilla
    Department of Clinical Sciences in Malmö, Lund University, Malmö.
    Agardh, Carl-David
    Department of Clinical Sciences in Malmö, Lund University, Malmö.
    Nilsson, Jan
    Department of Clinical Sciences in Malmö, Lund University, Malmö.
    Wamhoff, Brian R.
    Department of Medicine, University of Virginia, Charlottesville, VA, USA.
    Hultgårdh-Nilsson, Anna
    Department of Experimental Medical Science, Lund University, Lund.
    Gomez, Maria F
    Department of Clinical Sciences in Malmö, Lund University, Malmö.
    Nuclear Factor of Activated T Cells Regulates Osteopontin Expression in Arterial Smooth Muscle in Response to Diabetes-Induced Hyperglycemia2010In: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, ISSN 1079-5642, Vol. 30, no 2, p. 218-224Article in journal (Refereed)
    Abstract [en]

    Objective-Hyperglycemia is a recognized risk factor for cardiovascular disease in diabetes. Recently, we reported that high glucose activates the Ca2+/calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in arteries ex vivo. Here, we sought to determine whether hyperglycemia activates NFAT in vivo and whether this leads to vascular complications. Methods and Results-An intraperitoneal glucose-tolerance test in mice increased NFATc3 nuclear accumulation in vascular smooth muscle. Streptozotocin-induced diabetes resulted in increased NFATc3 transcriptional activity in arteries of NFAT-luciferase transgenic mice. Two NFAT-responsive sequences in the osteopontin (OPN) promoter were identified. This proinflammatory cytokine has been shown to exacerbate atherosclerosis and restenosis. Activation of NFAT resulted in increased OPN mRNA and protein in native arteries. Glucose-induced OPN expression was prevented by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. The calcineurin inhibitor cyclosporin A or the novel NFAT blocker A-285222 prevented glucose-induced OPN expression. Furthermore, diabetes resulted in higher OPN expression, which was significantly decreased by in vivo treatment with A-285222 for 4 weeks or prevented in arteries from NFATc3(-/-) mice. Conclusions-These results identify a glucose-sensitive transcription pathway in vivo, revealing a novel molecular mechanism that may underlie vascular complications of diabetes.

  • 37.
    Norddahl, Gudmundur L
    et al.
    Immunology Section, Institution for Experimental Medical Science, Lund University.
    Pronk, Cornelis J
    Immunology Section, Institution for Experimental Medical Science, Lund University.
    Wahlestedt, Martin
    Immunology Section, Institution for Experimental Medical Science, Lund University.
    Sten, Gerd
    Immunology Section, Institution for Experimental Medical Science, Lund University.
    Nygren, Jens M
    Immunology Section, Institution for Experimental Medical Science, Lund University.
    Ugale, Amol
    Immunology Section, Institution for Experimental Medical Science, Lund University.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Bryder, David
    Immunology Section, Institution for Experimental Medical Science, Lund University.
    Accumulating Mitochondrial DNA Mutations Drive Premature Hematopoietic Aging Phenotypes Distinct from Physiological Stem Cell Aging2011In: CELL STEM CELL, ISSN 1934-5909, Vol. 8, no 5, p. 499-510Article in journal (Refereed)
    Abstract [en]

    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 mitochondria! 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 mitochondria! DNA mutations per se being a primary driver of somatic stern cell aging.

  • 38.
    Norddahl, Gudmundur L
    et al.
    Lund University.
    Wahlestedt, Martin
    Lund University.
    Gisler, Santiago
    Lund University.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Bryder, David
    Lund University.
    Enhanced Cytokine Responsiveness Counteracts Age-Induced Decline in Hematopoietic Stem Cell Function in BLOOD, vol 118, issue 21, pp 1013-10132011In: BLOOD, American Society of Hematology , 2011, Vol. 118, no 21, p. 1013-1013Conference paper (Refereed)
    Abstract [en]

    n/a

  • 39.
    Norddahl, Gudmundurv L
    et al.
    Lund University, Sweden .
    Wahlestedt, Martin
    Lund University, Sweden .
    Gisler, Santiago
    Lund University, Sweden .
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Bryder, David
    Lund University, Sweden .
    Reduced repression of cytokine signaling ameliorates age-induced decline in hematopoietic stem cell function2012In: Aging Cell, ISSN 1474-9718, E-ISSN 1474-9726, Vol. 11, no 6, p. 1128-1131Article in journal (Refereed)
    Abstract [en]

    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.

  • 40.
    Persson, P
    et al.
    Lund University.
    Manetopoulos, C
    Lund University.
    Lagergren, A
    Lund University.
    Nygren, J
    Lund University.
    Gisler, R
    Lund University.
    Axelson, H
    Lund University.
    Sigvardsson, Mikael
    Lund University.
    Olf/EBF proteins are expressed in neuroblastoma cells: Potential regulators of the Chromogranin A and SCG10 promoters2004In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 110, no 1, p. 22-30Article in journal (Refereed)
    Abstract [en]

    The childhood malignancy neuroblastoma is derived from developmentally arrested sympathetic nervous system precursor cells. To obtain further insight into the molecular processes involved in the formation of these tumors, we decided to investigate the functional role of Olf/EBF (O/E) transcription factors in human neuroblastoma cells. We here report that O/E-1 and O/E-2 are expressed at variable levels in neuroblastoma cell lines and that O/E proteins could be identified by electrophoretic mobility shift assays. To identify potential neuronal target genes for O/E proteins in neuroblastoma cells we investigated the ability of a set of neuronal promoters to interact with O/E-1 in electrophoretic mobility shift assays. This analysis suggested that the Chromogranin A (CgA) and SCG10 promoters both contained binding sites for O/E-1. O/E-1 was able to activate the CgA promoter in vivo and mutation of the O/E-1 binding site in the CgA promoter reduced the functional activity of the element to about 60% of the wild-type in neuroblastoma cells, supporting the idea that O/E proteins may be involved in the control of the CgA promoter. Furthermore, overexpression of O/E-1 in hippocampal progenitor cells led to neurite outgrowth, indicative of a role for O/E proteins in neuronal differentiation.

  • 41. Prasad, Mahadesh A. J.
    et al.
    Ungerbäck, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Somasundaram, Rajesh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Strid, Tobias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Malin
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Mansson, Robert
    Karolinska Institute, Sweden.
    De Paepe, Ayla
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Lilljebjorn, Henrik
    Lund University, Sweden.
    Fioretos, Thoas
    Lund University, Sweden.
    Hagman, James
    National Jewish Heatlh, CO USA.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 125, no 26, p. 4052-4059Article in journal (Refereed)
    Abstract [en]

    Early B-cell factor 1 (Ebf1) is a transcription factor with documented dose-dependent functions in normal and malignant B-lymphocyte development. To understand more about the roles of Ebf1 in malignant transformation, we investigated the impact of reduced functional Ebf1 dosage on mouse B-cell progenitors. Gene expression analysis suggested that Ebf1 was involved in the regulation of genes important for DNA repair and cell survival. Investigation of the DNA damage in steady state, as well as after induction of DNA damage by UV light, confirmed that pro-B cells lacking 1 functional allele of Ebf1 display signs of increased DNA damage. This correlated to reduced expression of DNA repair genes including Rad51, and chromatin immunoprecipitation data suggested that Rad51 is a direct target for Ebf1. Although reduced dosage of Ebf1 did not significantly increase tumor formation in mice, a dramatic increase in the frequency of pro-B cell leukemia was observed in mice with combined heterozygous mutations in the Ebf1 and Pax5 genes, revealing a synergistic effect of combined dose reduction of these proteins. Our data suggest that Ebf1 controls DNA repair in a dose-dependent manner providing a possible explanation to the frequent involvement of EBF1 gene loss in human leukemia.

  • 42.
    Pron, C. J.
    et al.
    Lund University.
    Attema, J.
    Lund University.
    Rossi, D. J.
    Lund University.
    Sigvardsson, Mikael
    Lund University.
    Bryder, D.
    Lund University.
    Deciphering developmental stages of adult myelopoiesis2008In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 7, no 6, p. 706-713Article in journal (Refereed)
    Abstract [en]

    The ability to subfractionate minor cellular subsets by multiparameter flow cytometry and to evaluate such cells for functional properties has been used to ascertain lineal relationships and detail developmental hierarchies in the hematopoietic system for more than 20 years. However, steady advances in technology combined with the use of novel cell surface markers continues to redefine the developmental landscape as novel subpopulations are purified and characterized. We recently used such an approach to stage progenitor cell hierarchy involved in myeloid development with the use of two markers, Slamf1 and Endoglin that have recently been shown to be associated with hematopoietic stem cells. Here, we provide additional characterization of these cellular subsets to further refine their developmental potential. Little or no alterations in lineage potential were observed in these subsets when evaluated in a BCL2 transgenic setting or in response to various growth factor combinations, although BCL2 significantly enhanced their in vitro readout. Gene expression patterns of functionally opposing transcription factors that are known to play key roles for the appropriate development into separate myeloid lineages were associated with the functional activity of prospectively isolated subsets. Multiple genes traditionally associated with early lymphopoiesis were observed in early candidate granulocyte/monocyte, but not early megakaryocytic and/or erythroid progenitor cells. When functionally evaluated, such early granulocyte/monocyte precursors displayed a latent lymphoid activity, which was pronounced in subsets bearing high expression of the tyrosine kinase receptor FLT3. 

  • 43.
    Pronk, Cornelis J. H.
    et al.
    Lund University.
    Rossi, Derrick J.
    Stanford University School of Medicine.
    Månsson, Robert
    Lund University.
    Attema, Joanne L.
    Stanford University School of Medicine.
    Logi Norddahl, Gudmundur
    Lund University.
    Kwok Fai Chan, Charles
    Stanford University School of Medicine.
    Sigvardsson, Mikael
    Lund University.
    Weissman, Irving L.
    Stanford University School of Medicine.
    Bryder, David
    Lund University.
    Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy2007In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 1, no 4, p. 428-442Article in journal (Refereed)
    Abstract [en]

    The major myeloid blood cell lineages are generated from hematopoietic stem cells by differentiation through a series of increasingly committed progenitor cells. Precise characterization of intermediate progenitors is important for understanding fundamental differentiation processes and a variety of disease states, including leukemia. Here, we evaluated the functional in vitro and in vivo potentials of a range of prospectively isolated myeloid precursors with differential expression of CD150, Endoglin, and CD41. Our studies revealed a hierarchy of myeloerythroid progenitors with distinct lineage potentials. The global gene expression signatures of these subsets were consistent with their functional capacities, and hierarchical clustering analysis suggested likely lineage relationships. These studies provide valuable tools for understanding myeloid lineage commitment, including isolation of an early erythroid-restricted precursor, and add to existing models of hematopoietic differentiation by suggesting that progenitors of the innate and adaptive immune system can separate late, following the divergence of megakaryocytic/erythroid potential.

  • 44.
    Qian, Hong
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Badaloni, Aurora
    Ist Science San Raffaele, Italy .
    Chiara, Francesca
    Ist Science San Raffaele, Italy .
    Stjernberg, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Polisetti, Naresh
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Nihlberg, Kristian
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Giacomo Consalez, G
    Ist Science San Raffaele, Italy .
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Molecular Characterization of Prospectively Isolated Multipotent Mesenchymal Progenitors Provides New Insight into the Cellular Identity of Mesenchymal Stem Cells in Mouse Bone Marrow2013In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 33, no 4, p. 661-677Article in journal (Refereed)
    Abstract [en]

    Despite great progress in the identification of mesenchymal stem cells (MSCs) from bone marrow (BM), our knowledge of their in vivo cellular identity remains limited. We report here that cells expressing the transcription factor Ebf2 in 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 assays revealed their self-renewal and multilineage differentiation capacity. Gene expression analysis of the freshly sorted Ebf2(+) cells demonstrated the expression of genes previously reported to be associated with MSCs and the coexpression of multiple lineage-associated genes at the 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 completely overlap the previously reported MSC populations. These findings provide new insights into the in vivo cellular identity and molecular properties of BM mesenchymal stem and progenitor cells.

  • 45.
    Qian, Hong
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Le Blanc, Katarina
    Karolinska University Hospital, Sweden.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Primary Mesenchymal Stem and Progenitor Cells from Bone Marrow Lack Expression of CD44 Protein2012In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 31, p. 25795-25807Article in journal (Refereed)
    Abstract [en]

    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.

  • 46.
    Qian, Hong
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Early B-Cell Factor 2 Represents A Novel Marker of Highly Purified Messenchymal Stem-Like Cells in Mouse Bone Marrow in BLOOD, vol 114, issue 22, pp 107-1082009In: BLOOD, American Society of Hematology , 2009, Vol. 114, no 22, p. 107-108Conference paper (Refereed)
    Abstract [en]

    n/a

  • 47.
    Ramirez, Kevin
    et al.
    University of Chicago, USA .
    Chandler, Katherine J.
    University of Utah, USA .
    Spaulding, Christina
    University of Chicago, 15 USA .
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Graves, Barbara J.
    University of Utah, USA .
    Kee, Barbara L.
    University of Chicago, USA .
    Gene Deregulation and Chronic Activation in Natural Killer Cells Deficient in the Transcription Factor ETS12012In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 36, no 6, p. 921-932Article in journal (Refereed)
    Abstract [en]

    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, Ets(-/-) 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.

  • 48.
    Reyes, Jose L.
    et al.
    University of Calgary, Canada.
    Wang, Arthur
    University of Calgary, Canada.
    Fernando, Maria R.
    University of Calgary, Canada.
    Graepel, Rabea
    University of Calgary, Canada.
    Leung, Gabriella
    University of Calgary, Canada.
    van Rooijen, Nico
    Vrije University of Amsterdam, Netherlands.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    McKay, Derek M.
    University of Calgary, Canada.
    Splenic B Cells from Hymenolepis diminuta-Infected Mice Ameliorate Colitis Independent of T Cells and via Cooperation with Macrophages2015In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 194, no 1, p. 364-378Article in journal (Refereed)
    Abstract [en]

    Helminth parasites provoke multicellular immune responses in their hosts that can suppress concomitant disease. The gut lumen-dwelling tapeworm Hymenolepis diminuta, unlike other parasites assessed as helminth therapy, causes no host tissue damage while potently suppressing murine colitis. With the goal of harnessing the immunomodulatory capacity of infection with H. diminuta, we assessed the putative generation of anti-colitic regulatory B cells following H. diminuta infection. Splenic CD19(+) B cells isolated from mice infected 7 [HdBc(7(d))] and 14(d) (but not 3(d)) previously with H. diminuta and transferred to naive mice significantly reduced the severity of dinitrobenzene sulfonic acid (DNBS)-, oxazolone-, and dextran-sodium sulfate-induced colitis. Mechanistic studies with the DNBS model, revealed the anti-colitic HdBc(7(d)) was within the follicular B cell population and its phenotype was not dependent on IL-4 or IL-10. The HdBc(7(d)) were not characterized by increased expression of CD1d, CD5, CD23, or IL-10 production, but did spontaneously, and upon LPS plus anti-CD40 stimulation, produce more TGF-beta than CD19(+) B cells from controls. DNBS-induced colitis in RAG1(-/-) mice was inhibited by administration of HdBc(7(d)), indicating a lack of a requirement for T and B cells in the recipient; however, depletion of macrophages in recipient mice abrogated the anti-colitic effect of HdBc(7(d)). Thus, in response to H. diminuta, a putatively unique splenic CD19(+) B cell with a functional immunoregulatory program is generated that promotes the suppression of colitis dominated by TH1, TH2, or TH1-plus-TH2 events, and may do so via the synthesis of TGF-beta and the generation of, or cooperation with, a regulatory macrophage.

  • 49. Rolf, Julia
    et al.
    Berntman, Emma
    Stenström, Martin
    Smith, Emma M.K.
    Månsson, Robert
    Stenstad, Hanna
    Yamagata, Tetsuya
    Agace, William
    Sigvardsson, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology .
    Cardell, Susanna L.
    Molecular profiling reveals distinct functional attributes of CD1d-restricted natural killer (NK) T cell subsets2008In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 45, no 9, p. 2607-2620Article in journal (Refereed)
    Abstract [en]

    CD1d-restricted natural killer T (NKT) cells can have multiple effects on an immune response, including the activation, regulation and attraction of innate immune cells, and modulation of adaptive immunity. Recent studies reveal that there are distinct subsets of NKT cells which selectively perform some of the functions attributed to CD1d-restricted cells, but the mechanisms underlying these functional differences have not been resolved. Our aim in this study was to identify novel NKT cell associated traits that would provide important insight into NKT cell activation and function. To this end, we have performed gene expression profiling of two separate subsets of NKT cells, analyzing genes differentially expressed in these cells compared to conventional CD4+NK1.1- T cells. We identify different sets of genes over expressed in each of the two NKT cell types, as well as genes that are common to the two CD1d-restricted NKT cell populations analyzed. A large number of these genes are highly relevant for NKT cell development, activation and function. Each NKT subtype displayed a unique set of chemokine receptors, integrins and molecules related to effector function, supporting the notion that distinct NKT cells can be selectively engaged and have diverse functions in different types of immune reactions. © 2008 Elsevier Ltd. All rights reserved.

  • 50.
    Shi, CB
    et al.
    University of Lund Hospital.
    Zhao, X
    University of Lund Hospital.
    Lagergren, A
    Lund Strateg Centre Stem Cell Biol and Cell Therapy.
    Sigvardsson, Mikael
    Lund Strateg Centre Stem Cell Biol and Cell Therapy.
    Wang, XD
    Fudan University.
    Andersson, R
    University of Lund Hospital.
    Immune status and inflammatory response differ locally and systemically in severe acute pancreatitis2006In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 41, no 4, p. 472-480Article in journal (Refereed)
    Abstract [en]

    Objective. Acute pancreatitis ( AP) is an inflammatory disorder that develops a complex cascade of immunological events. The local and systemic immune status and inflammatory response might contribute to the understanding of underlying pathophysiological mechanisms and potential treatment. Material and methods. Severe AP was induced by intraductal perfusion of 5% sodium taurodeoxycholate in rats. mRNA expression of cytokines and chemokines was determined by reverse transcriptase- polymerase chain reaction ( RT- PCR) and NF- kappa B activation was assessed by electrophoretic mobility shift assay in fresh pancreatic acini and circulating monocytes 1, 3, 6 or 9 h after sham operation, induction of AP or N- acetylcysteine ( NAC) pretreatment. Flow cytometry was performed on cells obtained from the peripheral blood. Results. An inverse relationship in pancreatic and circulating monocytic NF- kappa B activation was detected 6 and 9 h after induction of AP. NAC further suppressed monocytic NF- kappa B activation induced by AP as seen 9 h after induction of AP. A marked constitutive increase in the expression of IL- 6, CINC and MCP- 1 was seen in pancreatic acini, whereas no change in mRNA expression of inflammatory mediators was observed in circulating monocytes 6 h after induction of AP. Flow cytometry further confirmed the altered function of circulating monocytes. Conclusions. The different immune status and inflammatory response in the pancreas and circulating monocytes improve the understanding of the mechanisms by which systemic inflammatory response syndrome ( SIRS) and multiple organ dysfunction syndrome ( MODS) develop in severe AP. A potential therapeutic approach could be to restore the functional capacity of the immune system in AP. The use of an NF kappa B inhibitor, preferentially reaching the local inflammatory foci, could be a potential future way of intervention.

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