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Träfflista för sökning "hsv:(MEDICIN OCH HÄLSOVETENSKAP) hsv:(Cell och molekylärbiologi) ;pers:(Sigvardsson Mikael)"

Sökning: hsv:(MEDICIN OCH HÄLSOVETENSKAP) hsv:(Cell och molekylärbiologi) > Sigvardsson Mikael

  • Resultat 1-10 av 41
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1.
  • Adolfsson, Jörgen, et al. (författare)
  • Identification of Flt3(+) lympho-myeloid stem cells lacking erythro-megakaryocytic potential: A revised road map for adult blood lineage commitment
  • 2005
  • Ingår i: Cell. - : Elsevier (Cell Press). - 0092-8674 .- 1097-4172. ; 121:2, s. 295-306
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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2.
  • Akerblad, P, et al. (författare)
  • Gene expression analysis suggests that EBF-1 and PPAR gamma 2 induce adipogenesis of NIH-3T3 cells with similar efficiency and kinetics
  • 2005
  • Ingår i: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 23:2, s. 206-216
  • Tidskriftsartikel (refereegranskat)abstract
    • Differentiation of multipotent mesenchymal stem cells into lipid-accumulating adipocytes is a physiological process induced by transcription factors in combination with hormonal stimulation. We have used Affymetrix microarrays to compare the adipogenic differentiation pathways of NIH-3T3 fibroblasts induced to undergo in vitro differentiation by ectopic expression of early B cell factor (EBF)-1 or peroxisome proliferator-activated receptor (PPAR)gamma 2. These experiments revealed that commitment to the adipogenic pathway in the NIH-3T3 cells was not reflected in gene expression until 4 days after induction of differentiation. Furthermore, gene expression patterns at the earlier time points after stimulation indicated that EBF-1 and PPAR gamma 2 induced different sets of genes, while the similarities increased upon differentiation, and that several genes linked to adipocyte differentiation were also transiently induced in the vector-transduced cells. These data suggest that the initial activation of genes associated with adipocyte development is independent of commitment to the adipogenic pathway and that EBF-1 and PPAR gamma 2 induce adipocyte differentiation with comparable kinetics and efficiency.
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3.
  • Bratengeier, Cornelia, 1983- (författare)
  • Mechanisms of mechanically induced Osteoclastogenesis : in a novel in vitro model for bone implant loosening
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Total joint arthroplasty is the primary intervention in the treatment of end-stage osteoarthritis. Despite the high success rate, in some patients, the replacement will fail during their lifetime requiring a revision of the implant. These revisions are strenuous for the patient and costly for health care. Joint replacement at a younger age, in combination with a more active lifestyle, increases the need for an early revision of the joint prosthesis. The main reason for revision surgeries is aseptic loosening, a condition where the prosthesis is loosening due to bone degradation at the peri-prosthetic interface in the absence of infections. The most well-established pathological mechanism for aseptic loosening is related to wear particles, generated from different parts of the prosthesis that will trigger bone degradation and bone loss. In addition, early micromotions of the prosthesis and resulting local pressurized fluid flow in the peri-prosthetic interface (supraphysiological loading) have also been identified as a cause for aseptic loosening. However, it remains unknown what cells are the primary responders to supraphysiological loading, and what underlying physical, cellular and molecular mechanism that triggers osteoclast differentiation and osteolysis.In this thesis, we intended to shed light on three currently unknown aspects of mechanical loading-induced peri-prosthetic osteolysis, leading to aseptic loosening of orthopedic prostheses: (1)Which cells are the primary responder to supraphysiological loading? (2)What characteristics of the mechanical stimulus induce an osteo-protective or osteo-destructive response? (3)Which cellular mechano-sensing mechanisms are involved in an osteo-destructive response?We successfully implemented supraphysiological mechanical loading, mimicking the periprosthetic pressurized fluid flow around a loosening implant, in an in vitro model for bone implant loosening. Using this model, we uncovered the involvement of mesenchymal stem cells and myeloid progenitor cells (monocytes) in mechanical loading-induced peri-prosthetic osteolysis. Applying supraphysiological loading on cells from patients undergoing primary hip arthroplasty, successfully validated the in vitro model for the use of cells of human origin. We further identified in murine myeloid progenitor cells that a combination of high loading amplitude (3.0±0.2Pa), prolonged active loading duration per cycle (duty cycle 22%-50%), and rapid alterations in minimum/maximum values of the loading profile (square wave) is necessary to induce an osteo-destructive response. Further, the loading-induced ATP release and subsequent activation of the P2X7 receptor was essential for the release of soluble factors modulating osteoclastogenesis.In conclusion, we expect that the proposed new in vitro model is a helpful tool to further advance the knowledge in aseptic loosening, by uncovering the mechanoresponsive cellular mechanism to supraphysiological mechanical loading. The identification of the respondent cells in mechanical loading-induced prosthetic loosening gives the opportunity to deliver targeted treatment strategies. Furthermore, identifying the physical parameters that define the shift towards an osteo-destructive response emphasizes the importance of the prosthetic design and surgical technique to reduce mechanical loading-induced bone degradation around a prosthesis.
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4.
  • Bryder, David, et al. (författare)
  • Shaping up a lineage-lessons from B lymphopoesis
  • 2010
  • Ingår i: CURRENT OPINION IN IMMUNOLOGY. - : Elsevier Science B.V., Amsterdam.. - 0952-7915 .- 1879-0372. ; 22:2, s. 148-153
  • Forskningsöversikt (refereegranskat)abstract
    • 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.
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5.
  • Davies, Lindsay C., et al. (författare)
  • Type 1 Diabetes Mellitus Donor Mesenchymal. Stromal Cells Exhibit Comparable Potency to Healthy Controls In Vitro
  • 2016
  • Ingår i: Stem Cells Translational Medicine. - : Oxford University Press (OUP). - 2157-6564 .- 2157-6580. ; 5:11, s. 1485-1495
  • Tidskriftsartikel (refereegranskat)abstract
    • Bone marrow mesenchymal stromal cells (BM-MSCs) have been characterized and used in many clinical studies based on their immunomodulatory and regenerative properties. We have recently reported the benefit of autologous MSC systemic therapy in the treatment of type 1 diabetes mellitus (T1D). Compared with allogeneic cells, use of autologous products reduces the risk of eliciting undesired complications in the recipient, including rejection, immunization, and transmission of viruses and prions; however, comparable potency of autologous cells is required for this treatment approach to remain feasible. To date, no analysis has been reported that phenotypically and functionally characterizes MSCs derived from newly diagnosed and late-stage T1D donors in vitro with respect to their suitability for systemic immunotherapy. In this study, we used gene array in combination with functional in vitro assays to address these questions. MSCs from T1D donors and healthy controls were expanded from BM aspirates. BM mononuclear cell counts and growth kinetics were comparable between the groups, with equivalent colony-forming unit-fibroblast capacity. Gene microarrays demonstrated differential gene expression between healthy and late-stage T1D donors in relation to cytokine secretion, immunomodulatory activity, and wound healing potential. Despite transcriptional differences, T1D MSCs did not demonstrate a significant difference from healthy controls in immunosuppressive activity, migratory capacity, or hemocompatibility. We conclude that despite differential gene expression, expanded MSCs from T1D donors are phenotypically and functionally similar to healthy control MSCs with regard to their immunomodulatory and migratory potential, indicating their suitability for use in autologous systemic therapy.
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6.
  • Dolinska, Monika, et al. (författare)
  • Characterization of the bone marrow niche in patients with chronic myeloid leukemia identifies CXCL14 as a new therapeutic option
  • 2023
  • Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
  • Tidskriftsartikel (refereegranskat)abstract
    • Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long -term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.
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7.
  • Fleenor, Courtney J., et al. (författare)
  • Zinc Finger Protein 521 Regulates Early Hematopoiesis through Cell-Extrinsic Mechanisms in the Bone Marrow Microenvironment
  • 2018
  • Ingår i: Molecular and Cellular Biology. - : AMER SOC MICROBIOLOGY. - 0270-7306 .- 1098-5549. ; 38:17
  • Tidskriftsartikel (refereegranskat)abstract
    • Zinc finger protein 521 (ZFP521), a DNA-binding protein containing 30 Kruppel-like zinc fingers, has been implicated in the differentiation of multiple cell types, including hematopoietic stem and progenitor cells (HSPC) and B lymphocytes. Here, we report a novel role for ZFP521 in regulating the earliest stages of hematopoiesis and lymphoid cell development via a cell-extrinsic mechanism. Mice with inactivated Zfp521 genes (Zfp521(-/-)) possess reduced frequencies and numbers of hematopoietic stem and progenitor cells, common lymphoid progenitors, and B and T cell precursors. Notably, ZFP521 deficiency changes bone marrow microenvironment cytokine levels and gene expression within resident HSPC, consistent with a skewing of hematopoiesis away from lymphopoiesis. These results advance our understanding of ZFP521s role in normal hematopoiesis, justifying further research to assess its potential as a target for cancer therapies.
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8.
  • Gioulbasani, Marianthi, et al. (författare)
  • The transcription factor BCL-6 controls early development of innate-like T cells
  • 2020
  • Ingår i: Nature Immunology. - : NATURE PUBLISHING GROUP. - 1529-2908 .- 1529-2916. ; 21, s. 1058-1069
  • Tidskriftsartikel (refereegranskat)abstract
    • Verykokakis and colleagues show that the transcription factor BCL-6 is highly expressed in stage 0 NKT and is absolutely required for innate T cell lineage development. BCL-6 acts to modify the chromatin landscape and is needed to promote the ST0-ST1 transition and PLZF expression. Innate T cells, including invariant natural killer T (iNKT) and mucosal-associated innate T (MAIT) cells, are a heterogeneous T lymphocyte population with effector properties preprogrammed during their thymic differentiation. How this program is initiated is currently unclear. Here, we show that the transcription factor BCL-6 was transiently expressed in iNKT cells upon exit from positive selection and was required for their proper development beyond stage 0. Notably, development of MAIT cells was also impaired in the absence ofBcl6. BCL-6-deficient iNKT cells had reduced expression of genes that were associated with the innate T cell lineage, includingZbtb16, which encodes PLZF, and PLZF-targeted genes. BCL-6 contributed to a chromatin accessibility landscape that was permissive for the expression of development-related genes and inhibitory for genes associated with naive T cell programs. Our results revealed new functions for BCL-6 and illuminated how this transcription factor controls early iNKT cell development.
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9.
  • Guzzi, Nicola, et al. (författare)
  • Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells
  • 2018
  • Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 173:5, s. 26-1216
  • Tidskriftsartikel (refereegranskat)abstract
    • Pseudouridylation (Ψ) is the most abundant and widespread type of RNA epigenetic modification in living organisms; however, the biological role of Ψ remains poorly understood. Here, we show that a Ψ-driven posttranscriptional program steers translation control to impact stem cell commitment during early embryogenesis. Mechanistically, the Ψ “writer” PUS7 modifies and activates a novel network of tRNA-derived small fragments (tRFs) targeting the translation initiation complex. PUS7 inactivation in embryonic stem cells impairs tRF-mediated translation regulation, leading to increased protein biosynthesis and defective germ layer specification. Remarkably, dysregulation of this posttranscriptional regulatory circuitry impairs hematopoietic stem cell commitment and is common to aggressive subtypes of human myelodysplastic syndromes. Our findings unveil a critical function of Ψ in directing translation control in stem cells with important implications for development and disease. Translational control in stem cells is orchestrated by pseudouridylation of specific tRNA-derived fragments, impacting stem cell commitment during key developmental processes.
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10.
  • Halvarsson, Camilla, 1985- (författare)
  • Hypoxia inducible factor 1 alpha : dependent and independent regulation of hematopoietic stem cells and leukemia
  • 2018
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • This thesis has studied the role of low oxygen levels, or hypoxia, in hematopoietic stem cells (HSCs) and how, at the molecular level, it regulates stem cell maintenance and protects against oxidative stress induced by reactive oxygen species (ROS). HSCs reside within the bone marrow in specific niches created by a unique vascularized environment, which is suggested to be hypoxic and crucial for HSCs by maintaining a quiescent state of cell cycle and by redirecting metabolism away from the mitochondria to glycolysis. The niches are also believed to limit the production of ROS, which could damage DNA and disrupt the stem cell features. The hypoxia-responsive protein hypoxia-inducible factor 1 alpha (HIF-1α) is a major regulator of the hypoxic cell response in HSCs as well as in leukemic stem cells. Both these cells are thought to reside in the bone marrow where they are protected from stress and chemotherapy by niche cells and hypoxia.The thesis demonstrates that pyruvate dehydrogenase kinase 1 regulates a metabolic shift to glycolysis, and maintains the engraftment potential of both HSCs and multipotent progenitors upon transplantation. Furthermore, we wanted to determine whether HIF-1α or other signaling pathways are involved in protecting HSCs from ROS-induced cell death. Overexpression, silencing or a knockout mouse model of Hif-1α could not identify HIF-1α as important for protecting HSCs from oxidative stress-induced cell death through inhibition of synthesis of the antioxidant glutathione. Gene expression analysis instead identified the transcription factor nuclear factor kappa B (NF-κB) as induced by hypoxia. By studying NF- κB signaling we found increased NF-κB activity in cells cultured in hypoxia compared to normoxia. Suppression of inhibitor of kappa B indicated a putative role of NF-κB signaling in hypoxia-induced protection against oxidative stress. The findings show that hypoxia-induced protection to elevated levels of ROS upon glutathione depletion seems to be attributed to activation of the NF-κB signaling pathway independently of HIF-1α.To address the question whether hypoxic in vitro cultures support maintenance and promote HSC expansion we performed a limited dilution-transplantation assay. Our data indicate that hypoxic cultures maintain more long-term-reconstituting HSCs than normoxia, but this could not be confirmed statistically. Finally, we wanted to study the mechanisms by which hypoxia protect against chemotherapy. We could demonstrate that hypoxic culture protects leukemic cell lines against apoptosis induced by chemotherapy or inhibitors used for treatment of leukemia. This multidrug resistance seems to be mediated by ATP-binding cassette transporter genes, which are upregulated by hypoxia and whose inhibition has been shown to increase chemosensitivity. In addition, HIF-1α was upregulated in the leukemic cell lines in hypoxia and its inhibition increased the sensitivity to chemotherapy, indicating a role in inducing chemotherapy resistance.Conclusively, the results presented in this thesis stress the importance of hypoxia in regulating metabolism, oxidative-stress response and maintenance of both HSCs as well as leukemic cells, especially through the critical transcription factors HIF-1α and NF-κB and their target genes.  
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