Erythropoietin mediates terminal granulocytic differentiation of committed myeloid cells with ectopic erythropoietin receptor expression.
OBJECTIVE
The precise role of hematopoietic cytokine/cytokine receptor interactions in lineage-restricted hematopoietic differentiation giving rise to mature blood cells of diverse function is incompletely defined. To study lineage-specific effects of cytokines during terminal hematopoietic differentiation, we examined the ability of erythropoietin (Epo) to mediate terminal granulocytic differentiation and induction of myeloid gene expression in committed myeloid cells, engineered to ectopically express Epo receptor (EpoR).


METHODS
A cell culture model for granulocyte-macrophage colony stimulating factor (GM-CSF)-mediated granulocytic differentiation was used. EpoR was introduced by retrovirus-mediated gene transfer into multipotential, hematopoietic murine cell line EML, from which GM-CSF-responsive, promyelocytic EPRO cells were generated. In EPRO cells ectopically expressing EpoR, we examined the ability of Epo to mediate granulocytic differentiation and determined whether Epo-mediated neutrophil differentiation is associated with a pattern of myeloid gene expression comparable to that induced by GM-CSF.


RESULTS
Studies of EpoR function in myeloid EPRO cells revealed that Epo/EpoR interaction can mediate terminal granulocytic differentiation of committed myeloid cells. In EPRO cells expressing EpoR, Epo-mediated neutrophil differentiation was associated with surface CD11b/CD18 (Mac-1) expression and induction of mRNA expression of specific myeloid genes including lactoferrin, gelatinase and C/EBPepsilon, in a manner similar to GM-CSF-mediated differentiation.


CONCLUSIONS
These results indicate that Epo can deliver differentiative signals along a non-erythroid lineage, providing evidence for interchangeable cytokine receptor signals that mediate terminal differentiation of committed myeloid cells.
Arcasoy
M O
MO
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. arcas001@mc.duke.edu
Maun
N A
NA
Perez
L
L
Forget
B G
BG
Berliner
N
N
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D002478:Cells, Cultured / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D016177:Macrophage-1 Antigen / Q000032:analysis; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D017467:Receptors, Erythropoietin / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology
D016177:Macrophage-1 Antigen; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D011993:Recombinant Fusion Proteins; D004921:Erythropoietin; D014212:Tretinoin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor