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(Journal of Leukocyte Biology. 2000;68:137-143.)
© 2000 by Society for Leukocyte Biology

Thrombopoietin enhances neutrophil production by bone marrow hematopoietic progenitors with the aid of stem cell factor in congenital neutropenia

Nobukuni Sawai^*, Kenichi Koike^*, Hadija Hemed Mwamtemi^*, Susumu Ito, Yumi Kurokawa^*, Kazuo Sakashita^*, Tatsuya Kinoshita^*, Tsukasa Higuchi^*, Kouichi Takeuchi^*, Masaaki Shiohara^*, Takehiko Kamijo^*, Yumiko Higuchi, Hiroshi Miyazaki, Takashi Kato, Masao Kobayashi^||, Munenori Miyake^**, Kozo Yasui^* and Atsushi Komiyama^*

^* Department of Pediatrics, Shinshu University School of Medicine, Matsumoto,
Blood Transfusion Service and
Central Clinical Laboratories, Shinshu University Hospital, Matsumoto;
Pharmaceutical Research Laboratory, Kirin Brewery Co. Ltd., Takasaki;
^|| Department of Pediatrics, Hiroshima University School of Medicine, Hiroshima; and
^** Department of Pediatrics, Osaka Medical College, Takatsuki, Japan

Correspondence: Kenichi Koike, M.D., Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan. E-mail: koikeken{at}hsp.md.shinshu-u.ac.jp

We examined the effects of granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), and thrombopoietin (TPO), alone or in combination, on the generation of neutrophils by bone marrow (BM) cells from three patients with severe congenital neutropenia (SCN) through the use of a serum-deprived liquid culture system. Synergistic effects of G-CSF and SCF on the neutrophil production by BM CD34⁺CD38⁺c-kit⁺ cells were observed in SCN patients as well as in normal controls. The addition of TPO to the culture containing G-CSF and SCF further augmented the growth of neutrophils in the two groups. Single-cell culture experiments revealed that the three-factor combination caused increases in both the number and size of neutrophil colonies compared with G-CSF + SCF in normal BM cells, whereas only a significant increment in the colony size was observed in SCN patients. Even in the presence of SCF or SCF + TPO, the concentrations of G-CSF necessary for the substantial production of neutrophils by CD34⁺CD38⁺c-kit⁺ cells were higher in two patients compared with the levels obtained by normal control cells. In addition, TPO did not accelerate the maturation of neutrophilic cells supported by G-CSF + SCF. When BM CD34⁺CD38^-c-kit⁺ cells were targeted, the addition of TPO to the culture containing G-CSF and SCF was required for significant neutrophil colony growth in the two groups. These results suggest that TPO enhances the G-CSF-dependent neutrophil production with the aid of SCF in this disorder.

Key Words: granulocyte colony-stimulating factor • CD34⁺CD38⁺ c-kit⁺ cells

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