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Thomas Jefferson University - Wolfgang Bergmeier, Ph.D.
Wolfgang Bergmeier, Ph.D.

Hematology
Assistant Professor

Thomas Jefferson University
Jefferson Medical College
Department of Medicine
Division of Hematology/ Cardeza Foundation
Mailing Address
1015 Walnut street, Curtis 702
Philadelphia, Pennsylvania 19107
United States
Contact Information
Phone: 215-955-2093
Fax: 215-923-3836
wolfgang.bergmeier@jefferson.edu
Expertise and Research Interests
Our research focuses on the adhesion mechanisms of platelets and neutrophils to sites of vascular injury/ activation. For successful adhesion, both cell types rely on activation-dependent receptors (integrins) expressed on the cell surface. We are particularly interested in the role of calcium (Ca2+) as a signaling molecule that regulates the inside-out activation of integrin receptors. Current research efforts are focused in three major areas:
1. Signaling events downstream of Ca2+. In recent studies, we were the first to identify CalDAG-GEFI as a signaling molecule critical to Ca2+-dependent integrin activation in platelets and neutrophils. Our studies further demonstrated that CalDAG-GEFI synergizes with protein kinase C (PKC) in the regulation of various aspects of platelet activation, including integrin activation and the generation of autocrine agonists such as thromboxane A2 and ADP. Consequently, mice lacking CalDAG-GEFI were characterized by a markedly impaired hemostatic and inflammatory response. We use various molecular, biochemical, and cellular strategies to better understand how CalDAG-GEFI function is regulated by Ca2+ and how it links Ca2+ to a range of responses triggered by cellular activation. We are currently also screening for small molecule inhibitors that could be used to interfere with CalDAG-GEFI function in the clinical settings of thrombosis and inflammation.
2. Molecules regulating Ca2+ influx in platelets and neutrophils. The intracellular Ca2+ concentration of many non-excitable cells is regulated by Ca2+ store release and store-operated Ca2+ entry (SOCE). We and others have recently identified STIM1 and Orai1 as critical regulators of SOCE in platelets. While STIM1 serves as a Ca2+ sensor in the endo-/sarco-plasmatic reticulum, Orai1 is the major Ca2+ channel expressed in the plasma membrane. In future studies, we hope to better understand how impaired STIM1/Orai1 function affects platelet function, especially with regard to responses regulated by CalDAG-GEFI.
3.Calcium signaling and ischemia-reperfusion injury. Myocardial Infarction (MI) and Deep Vein Thrombosis (DVT) are a national health concern, with over a million deaths per year. Reperfusion-induced tissue injury is a driving force of ischemic diseases such as MI and DVT. An important role for both leukocytes and platelets in the development of reperfusion injury has been described. We will evaluate how impaired Ca2+ signaling (CalDAG-GEFI, STIM1, Orai1) in platelets and/or neutrophils affects tissue damage in mouse models of reperfusion injury.
Publications
  • Stefanini L, Roden RC, Bergmeier W. CalDAG-GEFI is at the Nexus of Calcium-dependent Platelet Activation. Blood 2009, in press

  • Bergmeier W, Stefanini L. Novel molecules in calcium signaling in platelets. J Thromb Haemost. 2009, in press

  • Brill A, Chauhan AK, Canault M, Walsh MT, Bergmeier W, Wagner DD. Oxidative stress activates ADAM17/TACE and induces its target receptor shedding in platelets in a p38-dependent fashion. Cardiovasc Res 2009 [Epub ahead of print]

  • Bergmeier W, Oh-Hora M, McCarl CA, Roden RC, Bray PF, Feske S. R93W mutation in Orai1 causes impaired calcium influx in platelets. Blood 2009 Jan 15;113(3):675-8

  • Cifuni SM, Wagner DD, Bergmeier W. CalDAG-GEFI And Protein Kinase C (PKC) Represent Alternative Pathways Leading To Activation Of Integrin ±IIb²3 In Platelets. Blood 2008 Sep 1; 112(5):1696-703

  • Dole VS, Matuskova J, Vasile E, Yesilaltay A, Bergmeier W, Bernimoulin M, Wagner DD, Krieger M. Thrombocytopenia and Platelet Abnormalities in High-Density Lipoprotein Receptor-Deficient Mice. Arterioscler Thromb Vasc Biol. 2008 Jun;28(6):1111-6

  • Bergmeier W, Chauhan AK, Wagner DD. Glycoprotein Ibalpha and von Willebrand factor in primary platelet adhesion and thrombus formation: lessons from mutant mice. Thromb Haemost. 2008 Feb;99(2):264-70. Review.

  • Dole VS, Bergmeier W, Patten IS, Hirahashi J, Mayadas TN, Wagner DD. PSGL-1 regulates platelet P-selectin-mediated endothelial activation and shedding of P-selectin from activated platelets. Thromb Haemost. 2007 Oct;98(4):806-12

  • Bergmeier W, Goerge T, Wang HW, Crittenden JR, Baldwin ACW, Cifuni SM, Housman DE, Graybiel AM, Wagner DD. Mice lacking the signaling molecule, CalDAG-GEFI, represent a model for leukocyte adhesion deficiency type III. J Clin Invest. 2007 Jun;117(6):1699-707. Epub 2007 May 10.

  • Zhu L, Bergmeier W, Wu J, Jiang H, Stalker TJ, Cieslak M, Fan R, Boumsell L, Kumanogoh A, Kikutan H, Tamagnone L, Wagner DD, Milla ME, Brass LF. Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury. Proc Natl Acad Sci U S A 104(5):1621-1626, 2007. Epub 2007 Jan 23.

  • Babic AM, Josefsson EC, Bergmeier W, Wagner DD, Kaufman RM, Silberstein LE, Stossel TP, Hartwig JH, Hoffmeister KM. In vitro function and phagocytosis of galactosylated platelet concentrates after long-term refrigeration. Transfusion 47(3):442-451, 2007.

  • Chauhan AK, Kisucka J, Lamb CB, Bergmeier W, Wagner DD. von Willebrand Factor and Factor VIII are independently required to form stable occlusive thrombi in injured veins. Blood. 2007 Mar 15;109(6):2424-9. Epub 2006 Nov 21.

  • Bergmeier W, Piffath CL, Goerge T, Cifuni SM, Ruggeri ZM, Ware J, Wagner DD. The role of platelet adhesion receptor GPIb{alpha} far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis. Proc Natl Acad Sci U S A 103(45):16900-16905, 2006.

  • Chauhan AK, Motto DG, Lamb CB, Bergmeier W, Dockal M, Plaimauer B, Scheiflinger F, Ginsburg D, Wagner DD. Systemic antithrombotic effects of ADAMTS13. J Exp Med 203 (3):767-776, 2006

  • Bergmeier W and Wagner DD. Inflammation. In: Platelets, 2nd Edition, Michelson, A. (Ed.). San Diego: Elsevier/Academic Press, 2006.

  • Aktas B, Pozagajova M, Bergmeier W, Sunnarborg SW, Offermanns S, Lee DC, Wagner DD, Nieswandt B. Aspirin induces platelet receptor shedding via ADAM17 (TACE). J Biol Chem. 280(48):39716-22, 2005.

  • Dole VS, Bergmeier W, Mitchell HA, Eichenberger SC, Wagner DD. Activated platelets induce Weibel-Palade body secretion and leukocyte rolling in vivo: Role of P-selectin. Blood 106: 2334-2339, 2005.

  • Cai S, Dole VS, Bergmeier W, Scafidi J, Feng H, Wagner DD, Davis AE 3rd. A direct role for c1 inhibitor in regulation of leukocyte adhesion. J Immunol 174: 6462-6466, 2005.

  • Morrell CN, Matsushita K, Chiles K, Scharpf RB, Yamakuchi M, Mason RJ, Bergmeier W, Mankowski JL, Baldwin WM 3rd, Faraday N, Lowenstein CJ. Regulation of platelet granule exocytosis by S-nitrosylation. Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3782-7.

  • Schulze H, Korpal M, Bergmeier W, Italiano Jr, JE, Wahl SM, Shivdasani RA. Interactions between the megakaryocyte/platelet-specific ß1 tubulin and the secretory leukocyte protease inhibitor SLPI suggest a role for regulated proteolysis in platelet functions. Blood, 104(13):3949-57, 2004.

  • Crittenden JR*, Bergmeier W, Zhang Y, Piffath CL, Liang Y, Wagner DD, Housman DE, Graybiel AM. Calcium and diacylglycerol signaling through CalDAG-GEFI controls platelet aggregation. Nat Med, 10(9):982-6, 2004.

  • Bergmeier W, Piffath CL, Cheng G, Dole VS, Zhang Y, von Andrian UH, Wagner DD. Tumor Necrosis Factor-±-Converting Enzyme (ADAM17) Mediates GPIb± Shedding from Platelets In Vitro and In Vivo. Circ Res, 95(7):677-83, 2004.

  • Bergmeier W, Rabie T*, Strehl A, Piffath CL, Prostredna M, Wagner DD, Nieswandt B. GPVI down-regulation in murine platelets through metalloproteinase-dependent shedding. Thromb Haemost, 91(5):951-958, 2004.

  • Nieswandt B, Schulte V, and Bergmeier W. Flow cytometric analysis of mouse platelet activation. Methods Mol Biol, 272:255-68, 2004.

  • Cambien B, Bergmeier W, Saffaripour S, Wagner DD. Anti-thrombotic activity of TNF-±. J Clin Invest 112: 1589-1596, 2003.

  • Bergmeier W, Burger PC, Piffath CL, Hoffmeister KM, Hartwig JH, Nieswandt B, Wagner DD. Metalloproteinase inhibitors improve the recovery and hemostatic function of in vitro-aged or -injured mouse platelets. Blood 102: 4229-4235, 2003.

  • Poujol C, Bergmeier W, Nurden P, Nieswandt B, Nurden A. Effect of infusing rat monoclonal antibodies to the murine GPIb-IX-V complex on platelet and megakaryocyte morphology in mice. Platelets. 14:35-45, 2003.

  • Nieswandt B, Bergmeier W, Schulte V, Takai T, Baumann U, Schmidt RE, Zirngibl H, Bloch W, Gessner JE. Targeting of platelet integrin alphaIIbbeta3 determines systemic reaction and bleeding in murine thrombocytopenia regulated by activating and inhibitory FcgammaR. Int Immunol. 15:341-349, 2003.

  • Kuijpers MJ, Schulte V, Bergmeier W, Lindhout T, Brakebusch C, Offermanns S, Fassler R, Heemskerk JW, Nieswandt B. Complementary roles of glycoprotein VI and alpha2beta1 integrin in collagen-induced thrombus formation in flowing whole blood ex vivo. Faseb J.17:685-687, 2003.

  • Italiano JE, Jr., Bergmeier W, Tiwari S, Falet H, Hartwig JH, Hoffmeister KM, Andre P, Wagner DD, Shivdasani RA. Mechanisms and implications of platelet discoid shape. Blood. 101:4789-4796, 2003.

  • Hoffmeister KM, Felbinger TW, Falet H, Denis CV, Bergmeier W, Mayadas TN, von Andrian UH, Wagner DD, Stossel TP, Hartwig JH. The clearance mechanism of chilled blood platelets. Cell. 112:87-97, 2003.

  • Massberg S, Brand K, Gruner S, Page S, Muller E, Muller I, Bergmeier W, Richter T, Lorenz M, Konrad I, Nieswandt B, Gawaz M. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med. 196:887-896, 2002.

  • Bergmeier W, Schulte V, Brockhoff G, Bier U, Zirngibl H, Nieswandt B. Flow cytometric detection of activated mouse integrin alphaIIbbeta3 with a novel monoclonal antibody. Cytometry. 48:80-86, 2002

  • Schulte V, Snell D, Bergmeier W, Zirngibl H, Watson SP, Nieswandt B. Evidence for two distinct epitopes within collagen for activation of murine platelets. J Biol Chem. 276:364-368, 2001.

  • Nieswandt B, Brakebusch C*, Bergmeier W*, Schulte V, Bouvard D, Mokhtari-Nejad R, Lindhout T, Heemskerk JW, Zirngibl H, Fassler R. Glycoprotein VI but not alpha2beta1 integrin is essential for platelet interaction with collagen. Embo J. 20:2120-2130, 2001.

  • Nieswandt B, Bergmeier W, Eckly A, Schulte V, Ohlmann P, Cazenave JP, Zirngibl H, Offermanns S, Gachet C. Evidence for cross-talk between glycoprotein VI and Gi-coupled receptors during collagen-induced platelet aggregation. Blood. 97:3829-3835, 2001.

  • Nieswandt B, Schulte V, Bergmeier W, Mokhtari-Nejad R, Rackebrandt K, Cazenave JP, Ohlmann P, Gachet C, Zirngibl H. Long-term antithrombotic protection by in vivo depletion of platelet glycoprotein VI in mice. J Exp Med. 193:459-469, 2001.

  • Kauffenstein G, Bergmeier W, Eckly A, Ohlmann P, Leon C, Cazenave JP, Nieswandt B, Gachet C. The P2Y(12) receptor induces platelet aggregation through weak activation of the alpha(IIb)beta(3) integrin - a phosphoinositide 3- kinase-dependent mechanism. FEBS Lett. 505:281-290, 2001.

  • Bergmeier W, Bouvard D, Eble JA, Mokhtari-Nejad R, Schulte V, Zirngibl H, Brakebusch C, Fassler R, Nieswandt B. Rhodocytin (aggretin) activates platelets lacking alpha(2)beta(1) integrin, glycoprotein VI, and the ligand-binding domain of glycoprotein Ibalpha. J Biol Chem. 276:25121-25126, 2001.

  • Nieswandt B, Bergmeier W, Schulte V, Rackebrandt K, Gessner JE, Zirngibl H. Expression and function of the mouse collagen receptor glycoprotein VI is strictly dependent on its association with the FcRgamma chain. J Biol Chem. 275:23998-24002, 2000.

  • Nieswandt B, Bergmeier W, Rackebrandt K, Gessner JE, Zirngibl H. Identification of critical antigen-specific mechanisms in the development of immune thrombocytopenic purpura in mice. Blood. 96:2520-2527, 2000.

  • Bergmeier W, Rackebrandt K, Schroder W, Zirngibl H, Nieswandt B. Structural and functional characterization of the mouse von Willebrand factor receptor GPIb-IX with novel monoclonal antibodies. Blood. 95:886-893, 2000.

  • Viitanen P, Lorimer G, Bergmeier W, Weiss C, Kessel M, Goloubinoff P. Purification of mammalian mitochondrial chaperonin 60 through in vitro reconstitution of active oligomers. Methods Enzymol.98:2013-2217, 1999.

Individual Expertise profile of Wolfgang Bergmeier, Ph.D., Copyright © Wolfgang Bergmeier, Ph.D..
Last Updated by Wolfgang Bergmeier, Ph.D. : Friday, July 24, 2009 9:45:58 AM



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