Progenipoietin-1: a multifunctional agonist of the granulocyte colony-stimulating factor receptor and fetal liver tyrosine kinase-3 is a potent mobilizer of hematopoietic stem cells.
OBJECTIVE
Progenipoietin-1 is an agonist of both the granulocyte colony-stimulating factor and fetal liver tyrosine kinase-3 receptors capable of inducing the proliferation of multiple hematopoietic cell lineages. The potential of progenipoietin-1 to mobilize transplantable hematopoietic stem cells into the peripheral blood was evaluated.


METHODS
Cohorts of donor mice were treated with either progenipoietin-1, fetal liver tyrosine kinase-3 ligand, granulocyte colony-stimulating factor, or a vehicle control. Hematopoietic progenitor/stem-cell activity in donor blood was assayed by radioprotection, multilineage reconstitution, secondary transplantation, and competitive repopulation.


RESULTS
Only 1 microL of peripheral blood from progenipoietin-1-treated donors was required to protect 80% of lethally irradiated mice, while in contrast 1 microL of peripheral blood from granulocyte colony-stimulating factor-treated donors failed to protect any recipients. The radioprotected recipients of progenipoietin-1-treated donor cells showed donor-derived (Ly5.2) multilineage hematopoietic reconstitution for up to 6 months. Serial transplantation studies using bone marrow from radioprotected, chimeric recipients demonstrated long-term donor-derived hematopoiesis, indicating the successful transplantation of multipotent hematopoietic stem cells. The engraftment potential of progenipoietin-1 donor-derived cells was directly compared with donors treated with granulocyte colony-stimulating factor or fetal liver tyrosine kinase-3 ligand alone or in combination. Both spleen colony-forming activity and competitive repopulating activity was highest in the blood from progenipoietin-1-treated donors.


CONCLUSIONS
These studies demonstrate that progenipoietin-1 is a potent mobilizer of transplantable hematopoietic stem cells and indicate that this dual-receptor agonist has greater biologic activity than its constituent molecules.
Fleming
W H
WH
BMT Program, Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland, OR 97201-3098, USA. flemingw@ohsu.edu
Mulcahy
J M
JM
McKearn
J P
JP
Streeter
P R
PR
D000818:Animals; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology*; D008024:Ligands; D008099:Liver / Q000196:embryology / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011837:Radiation-Protective Agents / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000819:agonists*; D011994:Recombinant Proteins; D018183:Transplantation Chimera; D014184:Transplantation, Homologous / Q000502:physiology*; D051941:fms-Like Tyrosine Kinase 3
D003115:Colony-Stimulating Factors; D008024:Ligands; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011837:Radiation-Protective Agents; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; C084881:flt3 ligand protein; C434603:progenipoietin-1; D016179:Granulocyte Colony-Stimulating Factor; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3