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Simultaneous Activation of Signals Through gp130, c-kit, and Interleukin-3 Receptor Promotes a Trilineage Blood Cell Production in the Absence of Terminally Acting Lineage-Specific Factors
Takafumi Kimura,
Hideaki Sakabe,
Shigeatsu Tanimukai,
Tatsuo Abe,
Yoji Urata,
Kiyoshi Yasukawa,
Akira Okano,
Tetsuya Taga,
Haruo Sugiyama,
Tadamitsu Kishimoto, and
Yoshiaki Sonoda
From the Department of Hygiene, the Second Department of Surgery, and the First Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan; the Tokyo Research Center, Tosoh Co, Kanagawa, Japan; the Central Research Laboratories, Ajinomoto Co Inc, Yokohama, Japan; the Department of Molecular and Cellular Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; and the Departments of Clinical Laboratory Science and of Medicine III, Osaka University Medical School, Osaka, Japan.
We assessed the biologic role of signaling through gp130, a signal-transducing receptor (R) component, in human hematopoiesis in vitro. Although peripheral blood-derived CD34+ cells ubiquitously expressed gp130 and interleukin-3 receptor  (IL-3R), IL-6R was only detected on 80% of these CD34+ cells. We sorted CD34+IL-6R+ or CD34+IL-6R- cells and studied the effect on hematopoietic colony formation of signaling through gp130 activated by IL-6 or a combination of IL-6 and recombinant soluble human IL-6R (sIL-6R) in the presence or absence of stem cell factor (SCF ) and/or IL-3. Signals activated by SCF, IL-6, or IL-6/sIL-6R complex alone did not induce significant colony formation. However, a combination of IL-3, SCF, and IL-6/sIL-6R complex dramatically induced many neutrophil (colony-forming unit-granulocyte [CFU-G]), erythroid burst (burst-forming unit-erythrocyte [BFU-E]), erythrocyte-containing mixed (CFU-Mix), and megakaryocyte (CFU-Meg) colony formations when CD34+IL-6R- cells were used as the target. CFU-G colony formation induced by the three signals was more evident when CD34+IL-6R+ cells were used as the target. This distinct synergistic effect of the three different signals was confirmed by single-cell clone-sorting experiments. Moreover, colony formation (including CFU-G, BFU-E, CFU-Mix, and CFU-Meg) was observed even in the presence of neutralizing antibodies for granulocyte colony-stimulating factor, erythropoietin, and thrombopoietin (c-Mpl), whereas neutralizing antibodies for gp130, IL-6R, IL-3, and SCF partially or completely blocked the synergistic effect. The maturation of neutrophilic, erythroid, and megakaryocytic cells supported by the three signals in serum-free cultures was confirmed by immunostaining using anti-CD66b, antiglycophorin A, antihemoglobin , and anti-CD41 monoclonal antibodies, respectively. In contrast, any two of the three signals were insufficient for effective blood cell production in the absence of maturation factors. These results suggest that simultaneous activation of the three signals through gp130, c-kit, and IL-3R can induce in vitro proliferation and differentiation of trilineage hematopoietic progenitors in the absence of terminally acting lineage-specific factors.
Blood, Vol. 90 No. 12 (December 15), 1997:
pp. 4767-4778
© 1997 by The American Society of Hematology.
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