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-st imulating factor and fetal liver tyrosine kinase-3 receptors capable of ind ucing the proliferation of multiple hematopoietic cell lineages. The potent ial 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, f etal 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, seconda ry transplantation, and competitive repopulation. Results. Only 1 muL of peripheral blood from progenipoietin-1-treated donor s was required to protect 80% of lethally irradiated mice, while in contras t 1 muL of peripheral blood from granulocyte colony-stimulating factor-trea ted donors failed to protect any recipients. The radioprotected recipients of progenipoietin-1-treated donor cells showed donor-derived (Ly5.2) multil ineage hematopoietic reconstitution for up to 6 months. Serial transplantat ion studies using bone marrow from radioprotected, chimeric recipients demo nstrated long-term donor-derived hematopoiesis, indicating the successful t ransplantation or multipotent hematopoietic stem cells. The engraftment pot ential of progenipoietin-1 donor-derived cells was directly compared with d onors treated with granulocyte colony-stimulating factor or fetal liver tyr osine kinase-3 ligand alone or in combination. Both spleen colony-forming a ctivity and competitive repopulating activity was highest in the blood from progenipoietin-1-treated donors. Conclusion. These studies demonstrate that progenipoietin-1 is a potent mob ilizer of transplantable hematopoietic stem cells and indicate that this du al-receptor agonist has greater biologic activity than its constituent mole cules. (C) 2001 International Society for Experimental Hematology. Publishe d by Elsevier Science Inc.