Mobilized peripheral blood stem and progenitor cells (HSPC) are the preferred cell source for hematopoietic transplantation;however our understanding of the mobilization process is incomplete. Work by us and others using cellular and genetic models have identified a """"""""trans"""""""" acting component to mobilization by G-CSF and GRObeta, and the demonstration of a role for mature polymorphonuclear neutrophils (PMN) in mobilization. These studies have led to the hypothesis that release of proteases alters adhesive and intercellular interactions that result in peripheralization of HSPC. Although not proven, what is emerging is that mobilization is a complex process with broad interdependencies that can be stimulated by multiple mechanisms. We hypothesize that what appears to be multiple mechanisms, may in fact reflect multiple points of intervention along a central mobilization axis that includes adhesion co-receptors, chemokines and their receptors and interdependent inter and intracellular signaling components. We have identified a novel mobilization strategy utilizing the CXCR2 ligand GRObeta in combination with the CXCR4 antagonist AMD3100 that results in unexpected synergistic mobilization of HSPC with enhanced stem cell properties, and additional synergy when used in combination with G-CSF. We hypothesize that these cells may represent better hematopoietic grafts for transplant and gene therapy. Mechanism of mobilization studies lead us to a second hypothesis that synergistic mobilization results from unexpected receptor crosstalk between the CXCR4 and CXCR2 receptors that results in elevated and sustained PMN release of proteases, particularly MMP-9, that facilitates cell egress. We propose in this application to characterize the HSPC populations mobilized by GRObeta plus AMD3100 alone and with G-CSF, determine the mechanism of action of mobilization relative to PMN and MMP-9, and evaluate the utility of GRObeta plus AMD3100 mobilized HSPC as an improved hematopoietic cellular graft for hematopoietic transplant and gene therapy application. Project Relevance: Identifying regulatory pathways involved in stem cell mobilization will greatly enhance our knowledge of the stem cell niche and reward us with optimized procedures to collect populations of stem cells with enhanced properties that will positively impact stem cell transplantation and gene therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069669-08
Application #
7633246
Study Section
Special Emphasis Panel (ZRG1-HEME-A (02))
Program Officer
Thomas, John
Project Start
2001-08-15
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2011-05-31
Support Year
8
Fiscal Year
2009
Total Cost
$366,553
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Hoggatt, Jonathan; Singh, Pratibha; Tate, Tiffany A et al. (2018) Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell. Cell 172:191-204.e10
Hoggatt, Jonathan; Hoggatt, Amber F; Tate, Tiffany A et al. (2016) Bleeding the laboratory mouse: Not all methods are equal. Exp Hematol 44:132-137.e1
Fukuda, S; Hoggatt, J; Singh, P et al. (2015) Survivin modulates genes with divergent molecular functions and regulates proliferation of hematopoietic stem cells through Evi-1. Leukemia 29:433-40
Singh, Pratibha; Hoggatt, Jonathan; Hu, Peirong et al. (2012) Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells. Blood 119:1671-82
Hoggatt, Jonathan; Pelus, Louis M (2012) Hematopoietic stem cell mobilization with agents other than G-CSF. Methods Mol Biol 904:49-67
Singh, P; Hu, P; Hoggatt, J et al. (2012) Expansion of bone marrow neutrophils following G-CSF administration in mice results in osteolineage cell apoptosis and mobilization of hematopoietic stem and progenitor cells. Leukemia 26:2375-83
Broxmeyer, Hal E; Hoggatt, Jonathan; O'Leary, Heather A et al. (2012) Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis. Nat Med 18:1786-96
Pelus, L M; Hoggatt, J; Singh, P (2011) Pulse exposure of haematopoietic grafts to prostaglandin E2 in vitro facilitates engraftment and recovery. Cell Prolif 44 Suppl 1:22-9
Hoggatt, Jonathan; Pelus, Louis M (2011) Many mechanisms mediating mobilization: an alliterative review. Curr Opin Hematol 18:231-8
Pelus, Louis M; Hoggatt, Jonathan (2011) Pleiotropic effects of prostaglandin E2 in hematopoiesis; prostaglandin E2 and other eicosanoids regulate hematopoietic stem and progenitor cell function. Prostaglandins Other Lipid Mediat 96:3-9

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