Erythropoietin-independent erythrocyte production: signals through gp130 and c-kit dramatically promote erythropoiesis from human CD34+ cells.
Erythropoietin (EPO) is the primary humoral regulator of erythropoiesis and no other factor has previously been reported to support proliferation and terminal maturation of erythroid cells from hemopoietic stem cells. Here we show that stimulation of glycoprotein (gp130) by a combination of recombinant human soluble interleukin 6 receptor (sIL-6R) and IL-6 but not sIL-6R or IL-6 alone can support proliferation, differentiation, and terminal maturation of erythroid cells in the absence of EPO from purified human CD34+ cells in suspension culture containing stem cell factor (SCF). A number of erythroid bursts and mixed erythroid colonies also developed in methylcellulose culture under the same combination. The addition of anti-gp130 monoclonal antibodies but not anti-EPO antibody to the same culture completely abrogated the generation of erythroid cells. These results clearly demonstrate that mature erythroid cells can be emerged from hemopoietic progenitors without EPO in vitro. Together with the previous reports that human sera contain detectable levels of sIL-6R, IL-6, and SCF, current data suggest that gp130 signaling in association with c-kit activation may play a role in human erythropoiesis in vivo.
Sui
X
X
Department of Clinical Oncology, The Institute of Medical Science, The University of Tokyo, Japan.
Tsuji
K
K
Tajima
S
S
Tanaka
R
R
Muraoka
K
K
Ebihara
Y
Y
Ikebuchi
K
K
Yasukawa
K
K
Taga
T
T
Kishimoto
T
T
Nakahata
T
T
D015703:Antigens, CD / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D018952:Antigens, CD34 / Q000032:analysis* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D002999:Clone Cells; D050822:Cytokine Receptor gp130; D004912:Erythrocytes / Q000166:cytology*; D004920:Erythropoiesis; D004921:Erythropoietin / Q000494:pharmacology / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology*; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000502:physiology*; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology
D015703:Antigens, CD; D018952:Antigens, CD34; C494199:IL6ST protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D004921:Erythropoietin; D050822:Cytokine Receptor gp130; D019009:Proto-Oncogene Proteins c-kit