The ability to regulate hematopoiesis and to maintain hematopoietic balance is critical to the welfare of an organism, whether it is to meet additional demands to combat invading pathogens, or to re-establish the hematopoietic compartment subsequent to myelo-ablative events. Aging is accompanied by a general decline in hematopoietic capabilities, contributing to an increasing susceptibility to infections and to autoimmune conditions. A key parameter in the overall maintenance of the hematopoietic compartment is the residency of hematopoietic stem and progenitor cells (HSPCs) in the appropriate supportive marrow niches. Sialylated glycans participate in diverse cellular adhesive processes impacting multiple aspects of immunity and trafficking;however, little is known of the roles glycans play in early hematopoietic processes. Our laboratory has recently uncovered a novel biologic function for the sialyltransferase, ST6Gal-1, in the regulation of HSPC proliferation. There is compelling evidence that HSPC surfaces can be remodeled by extracellular ST6Gal-1, in a glycosylation pathway divergent from the canonical ER/Golgi-based pathway. The data point to the novel concept that extracellular glycosyltransferases generated from distal sources can function as """"""""systemic factors"""""""" in regulating hematopoiesis, putatively by the extracellular or extrinsic sialyl-modification of HSPC surface components. There are 4 Specific Aims. The first is to evaluate the impact of dysregulated ST6Gal-1 expression in the bone marrow hematopoietic compartment through the use of mice strains that differ only in the way they express ST6Gal-1.
The second aim i s to evaluate the relative contributions of the extrinsic and the canonical ER/Golgi-based pathways of ST6Gal-1 in sialylation of hematopoietic cell surfaces, with the ultimate aim of identifying the target molecules of extrinsic ST6Gal-1 action. The mechanism by which HSPCs are regulated by ST6Gal-1 will be the focus of Aim 3, through analysis of HSPC-stroma adhesion under static and flow-sheer conditions, and ST6Gal-1 impact on intracellular signaling pathways.
Aim 4 will evaluate the long-term impact of dysregulated ST6Gal-1 expression on hematopoietic capacities. The overall goal of this project is to understand the precise contribution and mechanism of ST6Gal-1 in the maintenance of hematopoietic functions, ultimately to yield glycan engineering strategies for effective modification of hematopoietic function.

Public Health Relevance

Hematopoiesis is the process through which bone marrow stem cells continuously regenerate all blood cell lineages while simultaneously self-renewing to replenish the stem cell pool. Regulating hematopoiesis is critical for meeting additional demands to combat invading pathogens and maintaining hematopoietic equilibrium. Ageing is accompanied by a decline in hematopoietic capabilities, contributing to an increased susceptibility to infections and autoimmune conditions. We have recently uncovered an entirely novel hematopoietic regulation pathway, mediated by the sialyltransferase, ST6Gal-1. We hypothesize those extracellular ST6Gal-1 functions as a systemic factor in regulating hematopoietic stem and progenitor cell behavior, putatively by the extracellular modification of hematopoietic cell surfaces. The overall goal of this project is to understand the contribution and mechanism of ST6Gal-1 in the maintenance of hematopoietic functions, ultimately to yield new treatments that effectively modify hematopoietic function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI056082-08
Application #
8645582
Study Section
Intercellular Interactions Study Section (ICI)
Program Officer
Minnicozzi, Michael
Project Start
2011-05-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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Lee-Sundlov, Melissa M; Ashline, David J; Hanneman, Andrew J et al. (2017) Circulating blood and platelets supply glycosyltransferases that enable extrinsic extracellular glycosylation. Glycobiology 27:188-198
Dougher, Christopher W L; Buffone Jr, Alexander; Nemeth, Michael J et al. (2017) The blood-borne sialyltransferase ST6Gal-1 is a negative systemic regulator of granulopoiesis. J Leukoc Biol 102:507-516
Wang, Min-Jun; Chen, Fei; Lau, Joseph T Y et al. (2017) Hepatocyte polyploidization and its association with pathophysiological processes. Cell Death Dis 8:e2805
Nasirikenari, Mehrab; Veillon, Lucas; Collins, Christine C et al. (2014) Remodeling of marrow hematopoietic stem and progenitor cells by non-self ST6Gal-1 sialyltransferase. J Biol Chem 289:7178-89
Lee, Melissa M; Nasirikenari, Mehrab; Manhardt, Charles T et al. (2014) Platelets support extracellular sialylation by supplying the sugar donor substrate. J Biol Chem 289:8742-8
Buffone Jr, Alexander; Mondal, Nandini; Gupta, Rohitesh et al. (2013) Silencing ?1,3-fucosyltransferases in human leukocytes reveals a role for FUT9 enzyme during E-selectin-mediated cell adhesion. J Biol Chem 288:1620-33
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Cabral, M Guadalupe; Silva, Zélia; Ligeiro, Dário et al. (2013) The phagocytic capacity and immunological potency of human dendritic cells is improved by ?2,6-sialic acid deficiency. Immunology 138:235-45
Jones, Mark B; Nasirikenari, Mehrab; Lugade, Amit A et al. (2012) Anti-inflammatory IgG production requires functional P1 promoter in ?-galactoside ?2,6-sialyltransferase 1 (ST6Gal-1) gene. J Biol Chem 287:15365-70

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