Hematopoietic stem cell transplant is a potentially curative therapy for hematologic and non-hematologic and genetic disorders;however limitations in stem cell number and function can affect engraftment rate and outcomes. In this proposal we will investigate the mechanism of action of eicosanoids in facilitating collection of stem cells and enhancing their engraftment and self-renewal upon transplantation. We believe that the information we derive can be directly translated to improve hematopoietic stem cell transplantation.Eicosanoids are physiological lipids that include prostaglandins, prostacyclins, thromboxanes, leukotrienes, and endocannabinoids. Our early studies demonstrated important negative and positive physiological roles forprostaglandin E2 (PGE2) in normal and abnormal hematopoiesis. Recent evidence suggests that short-term in vitro xposure to PGE2 can enhance the engraftment of hematopoietic stem and progenitor cells (HSPC). In this application, we present new preliminary findings that indicate that PGE2 can increase survival, homing and cell cycle rate of HSPC.
In specific aim 1, we will investigate the mechanism of action of PGE2 in enhancing HSPC engraftment and define the receptor subtype and signaling pathways responsible for PGE2-mediated enhancement of HSPC survival, homing and cell cycle and evaluate the role of other eicosanoids on HSC function. Bone marrow is a dynamic tissue and hematopoietic effects of PGE2 are complex and can be positive and negative and direct or amplified or mediated through accessory cells. We have extensively characterized the physiological roles PGE2 can play in cell proliferation and differentiation in vivo, at least at the progenitor cell level. However, given the ability we have today to precisely monitor HSC fate and function, it is critical to define the roles of endogenous and exogenous PGE2 within the host bone marrow in order to determine whether positive or negative modulation of PGE2 synthesis could further facilitate or potentially damage HSC engraftment.
In specific aim 2, we will evaluate the roles of endogenous PGE2 and other icosanoids on stem cell function and the hematopoietic microenvironment through the use of selective agonist/antagonist administration and/or selective blockade of PGE2 or alternate eicosanoid production in vivo. G-CSF mobilized peripheral blood stem cells are the primary hematopoietic graft in use for transplant today. Preliminary findings indicate that blockade of PG biosynthesis enhances mobilization by G-CSF and that endocannabinoids, members of the eicosanoid family with activities generally opposite that of the prostaglandins can also mobilize HPC and synergize with G-CSF.
In specific aim 3 we will evaluate the utility of eicosanoid pathway modulation for improved hematopoietic mobilization and transplantation and characterize the stem cell roperties of eicosanoid pathway mobilized cells.
Hematopoietic stem cell (HSC) transplantation is a curative therapy;but limitations in HSC number affects engraftment and outcome. Mobilized peripheral blood HSC are widely used, however poor mobilization in patients and normal donors occurs, resulting in inability to collect sufficient HSC. Umbilical cord blood is a relatively untapped source of HSC;however the total number of stem cells that can be obtained is usually too small for adult transplants. In this proposal we will investigate the mechanisms by which eicosanoids enhance HSC function and facilitate engraftment of HSC from all sources , as well as methods to modulate eicosanoid production and activity to obtain more HSC for transplant. If successful, the information we derive will greatly augment the ability to obtain more engraftable HSC and more efficiently deliver them to their marrow niches and can be rapidly and directly translated to improve hematopoietic stem cell transplantation.
|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|
|Broxmeyer, Hal E; Pelus, Louis M (2014) Inhibition of DPP4/CD26 and dmPGE? treatment enhances engraftment of mouse bone marrow hematopoietic stem cells. Blood Cells Mol Dis 53:34-8|
|Speth, Jennifer M; Hoggatt, Jonathan; Singh, Pratibha et al. (2014) Pharmacologic increase in HIF1* enhances hematopoietic stem and progenitor homing and engraftment. Blood 123:203-7|
|Hoggatt, Jonathan; Mohammad, Khalid S; Singh, Pratibha et al. (2013) Differential stem- and progenitor-cell trafficking by prostaglandin E2. Nature 495:365-9|
|Cutler, Corey; Multani, Pratik; Robbins, David et al. (2013) Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood 122:3074-81|
|Hoggatt, Jonathan; Singh, Pratibha; Stilger, Kayla N et al. (2013) Recovery from hematopoietic injury by modulating prostaglandin E(2) signaling post-irradiation. Blood Cells Mol Dis 50:147-53|
|Hoggatt, Jonathan; Mohammad, Khalid S; Singh, Pratibha et al. (2013) Prostaglandin E2 enhances long-term repopulation but does not permanently alter inherent stem cell competitiveness. Blood 122:2997-3000|
|Hoggatt, Jonathan; Pelus, Louis M (2013) How beneficial is the use of NSAIDs in stem-cell transplantation? Expert Opin Pharmacother 14:2453-6|
|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|
|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|
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