Infection secondary to neutropenia is a major cause of near-term morbidity and mortality in hematopoietic stem cell transplantation (HSCT) and in cancer therapeutics using myelosuppressive regimens. In each case, the recovery of hematopoiesis, heralded by return of granulocyte production. Is critically dependent on the combinatorial and temporal expression of adhesion molecules that create relevant myelopoietic growth niches within the marrow. Cell surface lactosaminyl glycans, particulariy those bearing terminal sialic acid and fucose modifications, serve as principal effectors, as well as modulators, of a variety of adhesive interactions essential to hematopoiesis. Conspicuously, the expression of these structures within hematopoietic cells of marrow varies distinctly in a stage-specific and lineage-specific manner. We hypothesize that changes In cell surface terminal lactosaminyl glycans help to specify the lineage fate of eariy hematopoietic progenitors, and, commensurately, proliferation and differentiation of these cells. In this project, we seek to define the terminal lactosaminyl glycans expressed on human cells among primitive progenitors, and eariy myeloid and non-myeloid progenitor subsets, obtained from sources relevant to hematopoietic stem cell transplantation (i.e., marrow, G-CSF-mobilized blood, cord blood), and the pertinent protein and/or lipid scaffolds that present these glycans. We will analyze the function(s) of terminal lactosaminyl glycans in licensing adhesive interactions critical to sustaining primitive hematopoietic cells and to driving eariy myelopoietic commitment, and, using a variety of biochemical techniques to remodel their expression, will directly examine how these structures affect hematopoietic processes, particularly myelopoietic proliferation and differentiation. We will also analyze how terminal lactosaminyl glycans mediate supportive interactions between hematopoietic stem cells and marrow stromal cells (""""""""mesenchymal stem cells"""""""", MSCs). These studies will address fundamental Issues regarding the glycobiology of hematopoiesis in humans. It is anticipated that the information obtained will yield transformative strategies to custom-modify expression of key terminal lactosaminyl glycans to achieve the overarching clinical goals of enhancing myelopoietic recovery following myelosuppressive/myeloablatlve chemoradiotherapy, of stimulating hematopoiesis in conditions of marrow failure, and of halting dysregulated myeloproliferation such as in leukemia.
Low levels of white blood cells can result In life-threatening infections. Deficiency of white blood cells is a common complication of cancer therapy and can also occur with bone marrow diseases. Information obtained from this research effort will provide important information on how white blood cells are made, and should pave the way for new treatments to increase white blood cell production when needed.
|Irons, Eric E; Lau, Joseph T Y (2018) Systemic ST6Gal-1 Is a Pro-survival Factor for Murine Transitional B Cells. Front Immunol 9:2150|
|Videira, Paula A; Silva, Mariana; Martin, Kyle C et al. (2018) Ligation of the CD44 Glycoform HCELL on Culture-Expanded Human Monocyte-Derived Dendritic Cells Programs Transendothelial Migration. J Immunol 201:1030-1043|
|Carrascal, Mylène A; Talina, Catarina; Borralho, Paula et al. (2018) Staining of E-selectin ligands on paraffin-embedded sections of tumor tissue. BMC Cancer 18:495|
|Mondal, Nandini; Dykstra, Brad; Lee, Jungmin et al. (2018) Distinct human ?(1,3)-fucosyltransferases drive Lewis-X/sialyl Lewis-X assembly in human cells. J Biol Chem 293:7300-7314|
|Donnelly, Conor; Dykstra, Brad; Mondal, Nandini et al. (2018) Optimizing human Treg immunotherapy by Treg subset selection and E-selectin ligand expression. Sci Rep 8:420|
|Carrascal, Mylène A; Silva, Mariana; Ramalho, José S et al. (2018) Inhibition of fucosylation in human invasive ductal carcinoma reduces E-selectin ligand expression, cell proliferation, and ERK1/2 and p38 MAPK activation. Mol Oncol 12:579-593|
|Silva, Mariana; Videira, Paula A; Sackstein, Robert (2017) E-Selectin Ligands in the Human Mononuclear Phagocyte System: Implications for Infection, Inflammation, and Immunotherapy. Front Immunol 8:1878|
|Manhardt, Charles T; Punch, Patrick R; Dougher, Christopher W L et al. (2017) Extrinsic sialylation is dynamically regulated by systemic triggers in vivo. J Biol Chem 292:13514-13520|
|Sackstein, Robert; Schatton, Tobias; Barthel, Steven R (2017) T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy. Lab Invest 97:669-697|
|Silva, Mariana; Fung, Ronald Kam Fai; Donnelly, Conor Brian et al. (2017) Cell-Specific Variation in E-Selectin Ligand Expression among Human Peripheral Blood Mononuclear Cells: Implications for Immunosurveillance and Pathobiology. J Immunol 198:3576-3587|
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