This application is in response to PAR-03-063 entitled: """"""""Competitive Supplement for Human Embryonic Stem Cell Research"""""""". The application is meant to supplement my HL67384 grant entitled: """"""""Cytokine Enhancement of Myeloid Progenitor Cell Survival"""""""".
One aim of this grant was to investigate the cellular effects of Stromal Cell Derived Factor. (SDF-1 = CXCL12) alone, and then in combination with either Flt3-Ligand (FL) or Thrombopoietin (TPO), on prolonging survival of human and murine myeloid progenitor cells (MPC) and murine stem cells and growth factor-dependent hematopoietic cell lines that undergo apoptosis upon withdrawal of growth factors.
The aims of this supplement, consistent with that of HL67384, are: 1) Define optimal culture conditions for growth and survival of human embryonic stem (HES) cells and their differentiation into embryoid bodies (EBs) containing MPC. Characteristic HES cells and HES cell-derived MPC for mRNA and surface expression of CXCR4 (receptor for SDF-1/CXCL12) and CD26 (dipeptidylpeptidase IV that can cleave SDF-1/CXCL 12 into an inactive truncated form). Since SDF-1/CXCL 1 synergizes with stem cell factor (SCF, also termed steel factor), thrombopoietin (TPO), or Flt3-1igand (FL) to enhance survival of MPC subjected to delayed addition of growth factors, characterize expression of c-kit (SCF-receptor), c-mI (TPO-receptor), and Flt-3 (FL-receptor) on HES cells and MPC found in EBs. 2) Evaluate influence of SDF-1/CXCL 12-CXCR4 axis and CD26 on enhancement of the survival/anti-apoptosis of HES cells and/or HES cell-derived MPC. Also, evaluate the effects of the SDF-1/CXCL12-CXCR4 axis in combination with SCF/c-kit, TPO/c-mpl, or FL/Flt-3 ligand-receptor interactions. These studies should increase current understanding of the cytokines/receptors involved in survival of HES and their hematopoietic cell progeny. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL067384-03S1
Application #
6743914
Study Section
Special Emphasis Panel (ZRG1-CDF-5 (50))
Program Officer
Thomas, John
Project Start
2001-06-15
Project End
2005-05-31
Budget Start
2003-09-22
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$75,250
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
Capitano, Maegan L; Broxmeyer, Hal E (2017) A role for intracellular and extracellular DEK in regulating hematopoiesis. Curr Opin Hematol 24:300-306
O'Leary, H A; Capitano, M; Cooper, S et al. (2017) DPP4 truncated GM-CSF and IL-3 manifest distinct receptor-binding and regulatory functions compared with their full-length forms. Leukemia 31:2468-2478
Lee, Man Ryul; Mantel, Charlie; Lee, Sang A et al. (2016) MiR-31/SDHA Axis Regulates Reprogramming Efficiency through Mitochondrial Metabolism. Stem Cell Reports 7:1-10
Broxmeyer, Hal E (2016) Enhancing the efficacy of engraftment of cord blood for hematopoietic cell transplantation. Transfus Apher Sci 54:364-72
Huang, X; Lee, M-R; Cooper, S et al. (2016) Activation of OCT4 enhances ex vivo expansion of human cord blood hematopoietic stem and progenitor cells by regulating HOXB4 expression. Leukemia 30:144-53
Broxmeyer, Hal E; Capitano, Maegan; Campbell, Timothy B et al. (2016) Modulation of Hematopoietic Chemokine Effects In Vitro and In Vivo by DPP-4/CD26. Stem Cells Dev 25:575-85
Messina-Graham, Steven; Broxmeyer, Hal (2016) SDF-1/CXCL12 modulates mitochondrial respiration of immature blood cells in a bi-phasic manner. Blood Cells Mol Dis 58:13-8
Broxmeyer, Hal E; O'Leary, Heather A; Huang, Xinxin et al. (2015) The importance of hypoxia and extra physiologic oxygen shock/stress for collection and processing of stem and progenitor cells to understand true physiology/pathology of these cells ex vivo. Curr Opin Hematol 22:273-8
Mantel, Charlie R; O'Leary, Heather A; Chitteti, Brahmananda R et al. (2015) Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock. Cell 161:1553-65
Capitano, Maegan L; Chitteti, Brahmananda R; Cooper, Scott et al. (2015) Ames hypopituitary dwarf mice demonstrate imbalanced myelopoiesis between bone marrow and spleen. Blood Cells Mol Dis 55:15-20

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