Denisa D. Wagner
Harvard Medical School
Program in Cellular and Molecular Medicine, Boston Children's Hospital
3 Blackfan Circle, CLSB Third Floor
Boston, MA 02115
Lab Members: 2 Instructors, 3 postdoctoral fellows, 1 graduate student, 1 visiting/exchange graduate student
Visit my lab page here.
My laboratory is interested in the rapid response of endothelial cells and blood cells to vascular injury. We have shown that endothelial cells store adhesion proteins, von Willebrand factor and P-selectin, in storage granules called Weibel-Palade bodies. Inflammatory stimuli (such as histamine) and injury stimuli (such as thrombin and fibrin) cause rapid exocytosis of the storage granules. To study the function of these molecules, we have prepared mice that are deficient in P-selectin or von Willebrand factor by homologous recombination in embryonic stem cells. The P-selectin-deficient mice have a pronounced defect in leukocyte interaction with the endothelium of the vessel wall and with activated platelets. von Willebrand factor-deficient mice have a prolonged bleeding time. We study these and other genetically engineered mice in experimental models of thrombosis, inflammation, and atherosclerosis and wound healing.
Endothelial cells treated with inflammatory cytokines synthesize another selectin: E-selectin, and similar to P-selectin, it also mediates binding to leukocytes. We prepared mice deficient in both P-and E-selectins. In contrast to the rather mild phenotypes observed in mice deficient in a single selectin gene, the doubly deficient mice exhibit extreme leukocytosis, elevated cytokine levels and alterations in hematopoiesis. Virtual lack of leukocyte rolling and low extravasation at sites of inflammation make these animals susceptible to opportunistic bacterial infections to which they succumb. The phenotype of these mice shows that the absence of endothelial selectins severely affects leukocyte homeostasis and indicates that these two selectins are as important for normal leukocyte function as the leukocyte ß2 integrins.
We have begun to study the role of neutrophil extracellular traps or NETs (decondensed chromatin ejected from neutrophil nuclei under stress) in pathological thrombosis. We found that NETs are a critical component of deep vein thrombosis. Our observation that cancers induce NETs explains the link of cancer to thrombosis. NETs are injurious to tissues and likely exacerbate many common inflammatory diseases. The extent to which inhibition of NETosis improves outcome in different pathologies involving inflammation and thrombosis is now the main topic of the lab’s investigations.
Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD, Jr., Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107(36):15880-15885. PMCID: 2936604.
Demers M, Ho-Tin-Noe B, Schatzberg D, Yang JJ, Wagner DD. Increased efficacy of breast cancer chemotherapy in thrombocytopenic mice. Cancer Res. 2011;71(5):1540-1549. PMCID: 3078642.
Demers M, Krause DS, Schatzberg D, Martinod K, Voorhees JR, Fuchs TA, Scadden DT, Wagner DD. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci U S A. 2012;109(32):13076-13081. PMCID: 3420209.
Thomas GM, Carbo C, Curtis BR, Martinod K, Mazo IB, Schatzberg D, Cifuni SM, Fuchs TA, von Andrian UH, Hartwig JH, Aster RH, Wagner DD. Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice. Blood. 2012;119(26):6335-6343. PMCID: 3383196.
Martinod K, Demers M, Fuchs TA, Wong SL, Brill A, Gallant M, Hu J, Wang Y, Wagner DD. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc Natl Acad Sci U S A. 2013;110(21):8674-8679. PMCID: 3666755.
For a complete listing of publications click here.
Last Update: 1/6/2014