ABSTRACT
Nearly 15 years have elapsed since the US Food and Drug Administration last approved a major new hematopoietic cytokine. Promiscuous binding to multiple receptors, or to receptors expressed by multiple tissues, reduces growth factor specificity and promotes side effects. Here we show that hematopoiesis can be differentially regulated using receptors rather than ligands. Conditional derivatives of both fibroblast growth factor receptor-1 (F36VFGFR1) and the thrombopoietin receptor (F36VMpl) induced a sustained expansion of mouse marrow cells ex vivo, and erythroid cells in vivo. Only F36VFGFR1 could support the ex vivo expansion of short-term repopulating hematopoietic stem cells (HSCs), the ex vivo survival of long-term repopulating HSCs, and the prolonged in vivo expansion of granulocytes, monocytes, and platelets. Only F36VMpl induced a response sufficiently rapid to accelerate recovery from radiation-induced anemia. These results establish receptors as a new class of hematopoietic regulators possessing activities unobtainable with growth factors.
Subject(s)
Hematopoiesis , Hematopoietic Stem Cells/metabolism , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Receptors, Thrombopoietin/metabolism , Amino Acid Substitution , Anemia/etiology , Anemia/genetics , Anemia/metabolism , Anemia/therapy , Animals , Bone Marrow Cells , Cell Survival/genetics , Erythroid Precursor Cells/cytology , Erythroid Precursor Cells/metabolism , Female , Genetic Therapy , Hematopoiesis/genetics , Hematopoietic Stem Cells/cytology , Leukocytes/cytology , Leukocytes/metabolism , Mice , Mice, Mutant Strains , Mutation, Missense , Radiation Injuries, Experimental/genetics , Radiation Injuries, Experimental/mortality , Radiation Injuries, Experimental/therapy , Receptor, Fibroblast Growth Factor, Type 1/genetics , Receptors, Thrombopoietin/genetics , Time Factors , Transduction, Genetic , Transplantation Chimera/genetics , Transplantation Chimera/metabolism , United States , United States Food and Drug AdministrationABSTRACT
Methods for specifically regulating transplanted cells have many applications in gene and cell therapy. We examined the response of human cord blood CD34+ cells to a specific mitotic signal in vivo. Using a conditional signaling molecule (F36VMpl) that is specifically activated by an artificial ligand called a chemical inducer of dimerization (CID), human hematopoietic cells transplanted into immune deficient mice were induced to proliferate. Only differentiating erythroid precursors and multipotential and erythroid progenitors (colony-forming unit [CFU]-mix and burst forming unitserythroid [BFUe]) responded; however, the nature of the response differed markedly between bone marrow and spleen. In the marrow, F36VMpl induced a 12- to 17-fold expansion of differentiated erythroid precursors and a loss of CFU-mix and BFUe. In the spleen, F36VMpl induced a marked rise in BFUe and CFU-mix and, relative to marrow, a much less prominent rise in more mature red cells. Clonal analysis was most consistent with the interpretation that the spleen and bone marrow differentially regulate the response of human progenitors to a mitotic signal, possibly influencing progenitor expansion versus differentiation. These findings establish CIDs as in vivo growth factors for human hematopoietic cells.
