Delayed platelet recovery, and attendant bleeding complications, is a major determinant of morbidity and mortality following myelosuppressive/myeloablatlve chemoradiotherapy. Hematopoiesis is critically dependent on the interplay of temporally expressed adhesion molecules that create relevant growth niches within the bone marrow. The stage-dependent display and function of distinct adhesion molecules is tightly controlled by hematopoietic cytokines and chemokines, which promote or inhibit hematopoietic stem cell (HSC) proliferation, differentiation, maturation and migration. These effects are mediated in part by modulation of cell surface lactosaminyl glycans, especially those containing terminal sialic acid and fucose modifications. Expression of these structures within hematopoietic marrow cells occurs in a stage-specific and lineage-specific fashion. In studies to date using mice deficient in the (pi,4)-galactosyltransferase, P4GalTl, we have obtained direct evidence that lactosaminyl glycans are key regulators of thrombopoiesis. In this project, we seek to define the distinct lactosaminyl glycans expressed on mouse and human megakaryocyte progenitors (MKPs) and megakaryocytes (MKs), and the pertinent protein scaffolds and lipids that present these glycans critical for thrombopoiesis. We will define the changes in surface lactosaminyl glycans induced by thrombopoletic chemokines and cytokines or bone marrow endothelial cells (BMECs), and examine how these lactosaminyl structures mediate adhesive interactions with BMECs critical to hematopoiesis in vitro and in vivo. To obtain knowledge translatable to practical therapeutic strategies, we will extend our studies to human cells to specifically determine how deficiency in p4GalT1 affects human thrombopoiesis and lactosaminoglycan surface expression. We will determine the pertinent protein scaffolds and lipids that present lactosaminoglycans critical for thrombopoiesis in human MKs and analyze the effects of chemokines and cytokines or BMECs on lactosaminoglycan expression. We will examine how changes in surface lactosaminoglycans on human MKs affect adhesive functions with BMECs in vitro and in vivo. These studies will address fundamental questions regarding the glycobiology of thrombopoiesis. We will also investigate the capacity of platelets to serve as mediators of extrinsic glycosylation. The generated information will serve to develop strategies to modulate expression of key terminal lactosaminyl glycans to enhance thrombopoiesis and platelet production following myelosuppressive/myeloablatlve chemoradiotherapy and in other conditions of thrombocytopenia, including bone marrow failure states.

Public Health Relevance

Bleeding complications following myelosuppressive/myeloablative chemoradiotherapy due to delayed platelet recovery are a major determinant of morbility and mortality. Increasing platelet production following myelosuppressive/myeloablative chemoradiotherapy will decrease the need for platelet transfusions and associated side effects, such as sepsis and antibody refractoriness to platelet transfusion.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL107146-03
Application #
8477247
Study Section
Special Emphasis Panel (ZHL1-CSR-H)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$527,723
Indirect Cost
$232,080
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Pachón-Peña, Gisela; Donnelly, Conor; Ruiz-Cañada, Catalina et al. (2016) A Glycovariant of Human CD44 is Characteristically Expressed on Human Mesenchymal Stem Cells. Stem Cells :
Dykstra, Brad; Lee, Jungmin; Mortensen, Luke J et al. (2016) Glycoengineering of E-Selectin Ligands by Intracellular versus Extracellular Fucosylation Differentially Affects Osteotropism of Human Mesenchymal Stem Cells. Stem Cells 34:2501-2511
Neelamegham, Sriram; Mahal, Lara K (2016) Multi-level regulation of cellular glycosylation: from genes to transcript to enzyme to structure. Curr Opin Struct Biol 40:145-152
Li, Renhao; Hoffmeister, Karin M; Falet, Hervé (2016) Glycans and the platelet life cycle. Platelets 27:505-11
Sackstein, Robert (2016) Fulfilling Koch's postulates in glycoscience: HCELL, GPS and translational glycobiology. Glycobiology 26:560-70
Yao, J; Zhang, L; Hu, L et al. (2016) Tumorigenic potential is restored during differentiation in fusion-reprogrammed cancer cells. Cell Death Dis 7:e2314
Hoffmeister, Karin M; Falet, Hervé (2016) Platelet clearance by the hepatic Ashwell-Morrell receptor: mechanisms and biological significance. Thromb Res 141 Suppl 2:S68-72
Xu, Yu-Xin; Ashline, David; Liu, Li et al. (2015) The glycosylation-dependent interaction of perlecan core protein with LDL: implications for atherosclerosis. J Lipid Res 56:266-76
Mondal, Nandini; Buffone Jr, Alexander; Stolfa, Gino et al. (2015) ST3Gal-4 is the primary sialyltransferase regulating the synthesis of E-, P-, and L-selectin ligands on human myeloid leukocytes. Blood 125:687-96
Grozovsky, Renata; Giannini, Silvia; Falet, Hervé et al. (2015) Regulating billions of blood platelets: glycans and beyond. Blood 126:1877-84

Showing the most recent 10 out of 48 publications