Human granulocyte-macrophage colony-stimulating factor (hGM-CSF)-dependent in vitro and in vivo proliferation and differentiation of all hematopoietic progenitor cells in hGM-CSF receptor transgenic mice.
To examine the relation between receptor expression and differentiation of hematopoietic cells, we produced transgenic mice that constitutively expressed the human granulocyte-macrophage colony stimulating factor (hGM-CSF) receptor at almost all stages of hematopoietic cell development. The high-affinity GM-CSF receptor is species specific, allowing analysis of the specific effects of hGM-CSF in our mouse model. Proliferation and differentiation of hematopoietic progenitor cells from transgenic mice were analyzed by means of methylcellulose colony-forming assay and in vivo treatment with hGM-CSF, respectively. We found that hGM-CSF supported various types of colonies, including granulocyte-macrophage, mast cell, megakaryocyte, blast cell, and mixed hematopoietic colonies, whereas mouse GM-CSF supported only granulocyte-macrophage colonies. In addition, hGM-CSF generated erythrocyte colonies in the absence of erythropoietin. Furthermore, in vivo administration of hGM-CSF to transgenic mice resulted in a dose-dependent increase in reticulocytes and white blood cells in the peripheral blood. The spleens of the mice showed gross enlargement, mainly caused by an increase of erythroid cells and their progenitors. Taken together, these results indicate that hGM-CSF receptor-mediated signals can support the growth of cells of all hematopoietic cell lineages if this receptor is present on the cell surface. This implies that the differentiation of hematopoietic progenitor cells is not determined by exogenous cytokine stimulation (instruction model) but by an intrinsic cell program in which cytokines simply select cells that express the appropriate receptor (stochastic model).
Nishijima
I
I
The Department of Molecular and Developmental Biology, Institute of Medical Science, The University of Tokyo, Japan.
Watanabe
S
S
Nakahata
T
T
Arai
K
K
D000818:Animals; D000941:Antigens / Q000032:analysis; D000954:Antigens, Surface; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology; D037181:Lectins, C-Type; D051379:Mice; D008822:Mice, Transgenic; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins / Q000032:analysis; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D013154:Spleen / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology
D000941:Antigens; D000954:Antigens, Surface; C527203:KLRB1 protein, human; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor