Thrombopoietin (TPO) via its receptor, c-mpl, is the primary physiological regulatory of platelet production. Because of this role in controlling platelet production via the megakaryocytic lineage, the TPO/c-mpl ligand-receptor pair is thought to act in a """"""""lineage dominant"""""""" fashion. Evidence from our group and others points to an expanded role for c-mpl and its ligand that includes the early stages of hematopoietic development. This expanded role for c-mpl/TPO in hematopoietic stem/progenitor cell function. An increased understanding of the role that c-mpl and its ligand play in stem/progenitor cell function could have a significant impact on bone marrow transplantation protocols used in the treatment of wide spectrum of human diseases. Recent work by our group demonstrates that c-mpl is expressed by a subset of cells enriched for primitive hematopoietic progenitor activity in both mouse and man. These findings suggest that in addition to its role in the biology of the megakaryocytic linages that c-mpl and its ligand also influences the biology of primitive hematopoietic stem/progenitor cells. We hypothesize that c-mpl expression demarcates a subset of CD34+CD38- cells capable of long-term lineages hematopoietic engraftment and self-renewal. In support of this hypothesis we have found that c-mpl is expressed by a subset of CD34+CD38- cells in adult bone marrow that can repopulate multiple lineages and CD34+ stem/progenitor cells in an in vivo assay for human hematopoiesis. To further test this hypothesis, we propose to define the developmental potential of CD34+CD38-mpl+ cells using in vivo assays for human hematopoiesis (SCID-hu Bone) and thymopoiesis (SCID-hu Thy/Liv) in immunodeficient mice. Specifically, we will: (1) Determine whether CD34+CD38-c-mpl+ cells are enriched for cells with long-term multi- lineage hematopoietic repopulating activity, (2) Determine whether CD34+CD38-c-mpl+ cells can develop into T-lymphoid cells and (3) Determine whether CD34+CD38-c-mpl+ cells have the capacity to self- renew.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK054767-04S1
Application #
6548309
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Badman, David G
Project Start
1999-02-01
Project End
2003-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
4
Fiscal Year
2002
Total Cost
$69,992
Indirect Cost
Name
University of South Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Tampa
State
FL
Country
United States
Zip Code
33612
Brooks, Robert; Fuhler, Gwenny M; Iyer, Sonia et al. (2010) SHIP1 inhibition increases immunoregulatory capacity and triggers apoptosis of hematopoietic cancer cells. J Immunol 184:3582-9
Perez, Lia E; Desponts, Caroline; Parquet, Nancy et al. (2008) SH2-inositol phosphatase 1 negatively influences early megakaryocyte progenitors. PLoS One 3:e3565
Kerr, William G (2008) A role for SHIP in stem cell biology and transplantation. Curr Stem Cell Res Ther 3:99-106
Desponts, C; Ninos, J M; Kerr, W G (2006) s-SHIP associates with receptor complexes essential for pluripotent stem cell growth and survival. Stem Cells Dev 15:641-6
Desponts, Caroline; Hazen, Amy L; Paraiso, Kim H T et al. (2006) SHIP deficiency enhances HSC proliferation and survival but compromises homing and repopulation. Blood 107:4338-45
Wang, Jia-Wang; Gamsby, Joshua J; Highfill, Steven L et al. (2004) Deregulated expression of LRBA facilitates cancer cell growth. Oncogene 23:4089-97
Ghansah, Tomar; Paraiso, Kim H T; Highfill, Steven et al. (2004) Expansion of myeloid suppressor cells in SHIP-deficient mice represses allogeneic T cell responses. J Immunol 173:7324-30
Wang, Jia-Wang; Howson, Julie M; Ghansah, Tomar et al. (2002) Influence of SHIP on the NK repertoire and allogeneic bone marrow transplantation. Science 295:2094-7
Tu, Z; Ninos, J M; Ma, Z et al. (2001) Embryonic and hematopoietic stem cells express a novel SH2-containing inositol 5'-phosphatase isoform that partners with the Grb2 adapter protein. Blood 98:2028-38
Greenberg, A W; Kerr, W G; Hammer, D A (2000) Relationship between selectin-mediated rolling of hematopoietic stem and progenitor cells and progression in hematopoietic development. Blood 95:478-86