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  • 1.
    Ahl, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Eriksson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sedin, John
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Schwan, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kreuger, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Turning Up the Heat: Local Temperature Control During in vivo Imaging of Immune Cells2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 2036Article in journal (Refereed)
    Abstract [en]

    Intravital imaging is an invaluable tool for studying the expanding range of immune cell functions. Only in vivo can the complex and dynamic behavior of leukocytes and their interactions with their natural microenvironment be observed and quantified. While the capabilities of high-speed, high-resolution confocal and multiphoton microscopes are well-documented and steadily improving, other crucial hardware required for intravital imaging is often developed in-house and less commonly published in detail. In this report, we describe a low-cost, multipurpose, and tissue-stabilizing in vivo imaging platform that enables sensing and regulation of local tissue temperature. The effect of tissue temperature on local blood flow and leukocyte migration is demonstrated in muscle and skin. Two different models of vacuum windows are described in this report, however, the design of the vacuum window can easily be adapted to fit different organs and tissues.

  • 2.
    Lomei, Jalal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Giraud, Antoine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Herrera Hidalgo, Carmen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Shibuya, Masabumi
    Jobu University, Gunma, Japan..
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Characterization of pro-angiogenic neutrophilsManuscript (preprint) (Other academic)
    Abstract [en]

    The roles of neutrophils in immune defense have been investigated for decades. These cells are well equipped to protect the body in several ways against invaders such as microorganism. Recently it has been reported that neutrophils also contribute to angiogenesis; they are recruited to the site of hypoxia where they can promote blood vessel formation, as demonstrated both in vivo and in vitro. We found that these neutrophils with proangiogenic actions form a specific subset of the circulating neutrophils. The proangiogenic neutrophils (PANs) exclusively express the adhesion molecule CD49d and vascular endothelial growth factor receptor 1 (VEGFR1), and contribute to angiogenesis by delivering MMP-9 (matrix metalloproteinase 9). In this study, PANs were compared to classic neutrophils in respect to physical features as well as functionality. We found that PANs in humans were smaller and in human and mice PANs had higher granularity compared to the classic neutrophils. Moreover, they were more efficient phagocytes than classic neutrophils. In the aortic ring model of angiogenesis, vessel neo-formation was increased by the presence of pro-angiogenic neutrophils. Finally, by using neutrophils from mice with impaired VEGFR1 receptor (Flt-1 tk-/- mice) we demonstrated the role of VEGFR1 in neutrophil recruitment towards angiogenic endothelium. Together these results show clear differences between the pro-angiogenic subpopulation and the classic neutrophils, which further solidify the conclusion of a specific neutrophil subpopulation.

  • 3.
    Massena, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vågesjö, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Seignez, Cédric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gustafsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Binet, François
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Herrera Hidalgo, Carmen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Giraud, Antoine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lomei, Jalal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Weström, Simone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Shibuya, Masabumi
    Jobu Univ, Gakubunkan Inst Physiol & Med, Gunma, Japan.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gerwins, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kreuger, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 17, p. 2016-2026Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor A (VEGF-A) is upregulated during hypoxia and is the major regulator of angiogenesis. VEGF-A expression has also been found to recruit myeloid cells to ischemic tissues where they contribute to angiogenesis. This study investigates the mechanisms underlying neutrophil recruitment to VEGF-A as well as the characteristics of these neutrophils. A previously undefined circulating subset of neutrophils shown to be CD49d(+)VEGFR1(high)CXCR4(high) was identified in mice and humans. By using chimeric mice with impaired VEGF receptor 1 (VEGFR1) or VEGFR2 signaling (Flt-1tk(-/-), tsad(-/-)), we found that parallel activation of VEGFR1 on neutrophils and VEGFR2 on endothelial cells was required for VEGF-A-induced recruitment of circulating neutrophils to tissue. Intravital microscopy of mouse microcirculation revealed that neutrophil recruitment by VEGF-A versus by the chemokine macrophage inflammatory protein 2 (MIP-2 [CXCL2]) involved the same steps of the recruitment cascade but that an additional neutrophil integrin (eg, VLA-4 [CD49d/CD29]) played a crucial role in neutrophil crawling and emigration to VEGF-A. Isolated CD49d(+) neutrophils featured increased chemokinesis but not chemotaxis compared with CD49d(-) neutrophils in the presence of VEGF-A. Finally, by targeting the integrin α4 subunit (CD49d) in a transplantation-based angiogenesis model that used avascular pancreatic islets transplanted to striated muscle, we demonstrated that inhibiting the recruitment of circulating proangiogenic neutrophils to hypoxic tissue impairs vessel neoformation. Thus, angiogenesis can be modulated by targeting cell-surface receptors specifically involved in VEGF-A-dependent recruitment of proangiogenic neutrophils without compromising recruitment of the neutrophil population involved in the immune response to pathogens.

  • 4.
    Nikpour, Maryam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gustafsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vågesjö, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Giraud, Antoine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Shb deficiency in endothelium but not in leukocytes is responsible for impaired vascular performance during hindlimb ischemia.2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 214, no 2, p. 200-209Article in journal (Refereed)
    Abstract [en]

    Aim: Myeloid cells have been suggested to participate in angiogenesis and regulation of vascular function. Shb-deficient mice display both vascular and myeloid cell abnormalities with possible consequences for recovery after hindlimb ischemia. This study was conducted in order to assess the contribution of Shb-deficiency in myeloid cells to impaired vascular function in ischemia. Methods: Wild type and Shb-deficient mice were subjected to peritoneal VEGFA followed by intraperitoneal lavage, after which blood and peritoneal cells were stained for myeloid markers. VEGFA-induced leukocyte recruitment to cremaster muscle was investigated using intravital microscopy of both mouse strains. Blood flow after femoral artery ligation was determined on chimeric mice after bone marrow transplantation. Results: No differences in neutrophil numbers or cell surface phenotypes were detected. Moreover, neutrophil extravasation in VEGFA-activated cremaster muscle was unaffected by Shb deficiency. However, blood and peritoneal CXCR4+ monocytes/macrophages were reduced in response to intraperitoneal VEGFA but not LPS in the absence of Shb. Furthermore, the macrophage population in ischemic muscle was unaffected by Shb-deficiency after two days but reduced seven days after injury. The bone marrow transplantation experiments revealed that mice with wild type vasculature showed better blood flow than those with Shb-deficient vasculature irrespective of leukocyte genotype. Conclusion: The observed aberrations in myeloid cell properties in Shb-deficient mice are likely consequences of an abnormal vascular compartment and are not responsible for reduced muscle blood flow. Structural vascular abnormalities seem to be the primary cause of poor vascular performance under provoked vascular stress in this genetic model.

  • 5.
    Parv, Kristel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Herrera Hidalgo, Carmen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Elucidating the dynamics and role of peri-vascular macrophages2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 82-83Article in journal (Other academic)
  • 6.
    Seignez, Cedric
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Implanted biomaterials: Neutrophil-mediated vascularization2017In: NATURE BIOMEDICAL ENGINEERING, ISSN 2157-846X, Vol. 1, no 6, article id UNSP 0086Article in journal (Other academic)
  • 7.
    Seignez, Cedric
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    The multitasking neutrophils and their involvement in angiogenesis2017In: Current opinion in hematology, ISSN 1065-6251, E-ISSN 1531-7048, Vol. 24, no 1, p. 3-8Article, review/survey (Refereed)
    Abstract [en]

    Purpose of reviewThis review describes the mechanisms by which neutrophils contribute to angiogenesis in hypoxic tissues during different conditions and diseases (e.g., menstrual cycle, wound healing, ischemic diseases, cancers), with particular focus on the recently described proangiogenic neutrophil subpopulation.Recent findingsThe importance of neutrophils in initiation of angiogenesis has been described during the past decade, and is believed to occur through release of the well-known proangiogenic factors Bv8, vascular endothelial growth factor A, and matrix metalloproteinase 9. However, additional proangiogenic actions of neutrophils have been outlined this year, mediated through for example pyruvate kinase M2, 14,15-epoxyeicosatrienoic acid, and formation of neutrophil extracellular traps, although their distinct mechanisms of action remain partly unknown. Neutrophils can also limit angiogenesis by secreting for example neutrophil elastase and -defensins, which generate angiostatic molecules and proteolytically inactivate proangiogenic factors, respectively. These opposing neutrophil actions can be the consequence of on-site education or recruitment of distinct subpopulations from circulation. Indeed, a circulating proangiogenic neutrophil subpopulation was recently described in mice and men, which was rapidly recruited to hypoxic tissues by vascular endothelial growth factor A.SummaryThese recent findings have highlighted the diversity of actions performed by neutrophils in the angiogenic process and identified new opportunities to regulate angiogenesis.

  • 8.
    Seignez, Cedric
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Tissue hypoxia induces the mobilisation from the spleen of pro-angiogenic neutrophils through the activation of sympathetic nerves2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 78-78Article in journal (Other academic)
  • 9.
    Thålin, Charlotte
    et al.
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Div Internal Med, Stockholm.
    Lundström, Staffan
    Stockholms Sjukhem Fdn, Palliat Care Serv, Stockholm; Karolinska Inst, Dept Oncol Pathol, Stockholm.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Daleskog, Maud
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Div Internal Med, Stockholm.
    Lundström, Annika
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Div Internal Med, Stockholm.
    Henriksson, Peter
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm.
    Helleday, Thomas
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Wallen, Håkan
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm.
    Demers, Melanie
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Div Internal Med, Stockholm.
    Citrullinated histone H3 as a novel prognostic blood marker in patients with advanced cancer2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 1, article id e0191231Article in journal (Refereed)
    Abstract [en]

    Citrullinated histone H3 (H3Cit) is a central player in the neutrophil release of nuclear chromatin, known as neutrophil extracellular traps (NETs). NETs have been shown to elicit harmful effects on the host, and were recently proposed to promote tumor progression and spread. Here we report significant elevations of plasma H3Cit in patients with advanced cancer compared with age-matched healthy individuals. These elevations were specific to cancer patients as no increase was observed in severely ill and hospitalized patients with a higher non-malignant comorbidity. The analysis of neutrophils from cancer patients showed a higher proportion of neutrophils positive for intracellular H3Cit compared to severely ill patients. Moreover, the presence of plasma H3Cit in cancer patients strongly correlated with neutrophil activation markers neutrophil elastase (NE) and myeloperoxidase (MPO), and the inflammatory cytokines interleukin-6 and -8, known to induce NETosis. In addition, we show that high levels of circulating H3Cit strongly predicted poor clinical outcome in our cohort of cancer patients with a 2-fold increased risk for short-term mortality. Our results also corroborate the association of NE, interleukin-6 and -8 with poor clinical outcome. Taken together, our results are the first to unveil H3Cit as a potential diagnostic and prognostic blood marker associated with an exacerbated inflammatory response in patients with advanced cancer.

  • 10.
    Vågesjö, Evelina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Herrera Hidalgo, Carmen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Giraud, Antoine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rundqvist, H.
    Karolinska Inst, Cell & Mol Biol Dept, Solna, Sweden.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Johnson, R.
    Karolinska Inst, Cell & Mol Biol Dept, Solna, Sweden; Univ Cambridge, Physiol Dev & Neurosci Dept, Cambridge, England.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Perivascular macrophages regulate blood flow following tissue damage2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 44-45Article in journal (Other academic)
  • 11.
    Vågesjö, Evelina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Eriksson, Ulf J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Uncovering a new role for immune cells: macrophages assist in regulation of blood flow in ischemic muscleManuscript (preprint) (Other academic)
  • 12.
    Yan, Hongji
    et al.
    AlbaNova Univ Ctr, KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Div Glycosci,Dept Chem, S-10691 Stockholm, Sweden.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hjorth, Morgan
    AlbaNova Univ Ctr, KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Div Glycosci,Dept Chem, S-10691 Stockholm, Sweden.
    Winkeljann, Benjamin
    Tech Univ Munich, Dept Mech Engn, Boltzmannstr 11, D-85748 Garching, Germany;Tech Univ Munich, Munich Sch Bioengn, Boltzmannstr 11, D-85748 Garching, Germany.
    Blakeley, Matthew
    AlbaNova Univ Ctr, KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Div Glycosci,Dept Chem, S-10691 Stockholm, Sweden.
    Lieleg, Oliver
    Tech Univ Munich, Dept Mech Engn, Boltzmannstr 11, D-85748 Garching, Germany;Tech Univ Munich, Munich Sch Bioengn, Boltzmannstr 11, D-85748 Garching, Germany.
    Phillipson, Mia
    Uppsala Univ, Dept Med Cell Biol, Div Integrat Physiol, S-75123 Uppsala, Sweden.
    Crouzier, Thomas
    AlbaNova Univ Ctr, KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Div Glycosci,Dept Chem, S-10691 Stockholm, Sweden.
    Immune-Informed Mucin Hydrogels Evade Fibrotic Foreign Body Response In Vivo2019In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 29, no 46, article id 1902581Article in journal (Refereed)
    Abstract [en]

    The immune-mediated foreign body response to biomaterial implants can trigger the formation of insulating fibrotic capsules that can compromise implant function. To address this challenge, the intrinsic bioactivity of the mucin biopolymer, a heavily glycosylated protein that forms the protective mucus gel covering mucosal epithelia, is leveraged. By using a bioorthogonal inverse electron demand Diels-Alder reaction, mucins are crosslinked into implantable hydrogels. It is shown that mucin hydrogels (Muc-gels) modulate the immune response driving biomaterial-induced fibrosis. Muc-gels do not elicit fibrosis 21 days after implantation in the peritoneal cavity of C57Bl/6 mice, whereas medical-grade alginate hydrogels are covered by fibrous tissues. Further, Muc-gels dampen the recruitment of innate and adaptive immune cells to the gel and trigger a pattern of very mild activation marked by a noticeably low expression of the fibrosis-stimulating transforming growth factor beta 1 cytokine. Macrophages recruited to Muc-gels upregulate the gene expression of the protein inhibitor of activated STAT 1 (PIAS1) and SH2-containing phosphatase 1 (SHP-1) cytokine regulatory proteins, which likely contributes to their low cytokine expression profiles. With this advance in mucin materials, an essential tool is provided to better understand mucin bioactivities and to initiate the development of new mucin-based and mucin-inspired "immune-informed" materials for implantable devices subject to fibrotic encapsulation.

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