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Induction of c-kit Molecules on Human CD34⁺/c-kit^<low Cells: Evidence for CD34⁺/c-kit^<low Cells as Primitive Hematopoietic Stem Cells

^a Cellular Technology Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan;
^b First Department of Pathology,
^c Department of Pediatrics,
^d Department of Obstetrics and Gynecology, Kansai Medical University, Moriguchi City, Osaka, Japan

Key Words. c-kit • CD34 • Human cord blood • Hematopoietic stem cells

Dr. Susumu Ikehara, First Department of Pathology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi City, Osaka 570, Japan.

c-kit, a receptor for stem cell factor, has been widely accepted as a distinctive marker for hematopoietic stem cells. However, the level of c-kit expression on pluripotent hematopoietic stem cells is still controversial in mice and humans. We purified CD34⁺/c-kit^<low cells (phenotypically c-kit-negative but only detectable at the message level) from human cord blood and examined their maturational steps in relation to the expression of c-kit molecules. When the CD34⁺/c-kit^<low cells were cultured with cytokines (flt 3 ligand, interleukin 6 and interleukin 7) plus immobilized anti-CD34 monoclonal antibody (to crosslink CD34 molecules), c-kit molecules were clearly induced within 24 h. The c-kit expression gradually increased until day 8. When CD34⁺/c-kit^low or CD34⁺/c-kit⁺ cells that had been induced from CD34⁺/c-kit^<low cells were resorted and recultured using a methylcellulose culture system, they showed the same colony-forming ability as the freshly isolated CD34⁺/c-kit^low or CD34⁺/c-kit⁺ cells, respectively. Furthermore, CD34⁺/c-kit^<low cells have a similar hematopoietic potential to CD34⁺/c-kit^low cells in assays for long-term culture initiating cell and colony-forming unit culture generated from long-term cultures. These findings suggest that CD34⁺/c-kit^<low cells mature into CD34⁺/c-kit^low and CD34⁺/c-kit⁺ cells, and acquire the reactivity to various humoral hematopoietic stimuli. Moreover, CD34⁺/c-kit^<low cells showed a low level of rhodamine 123 retention, suggesting that CD34⁺/c-kit^<low cells have multidrug resistance. Therefore, the CD34⁺/c-kit^<low cells without colony-forming unit-granulocyte-erythroid-macrophage-megakaryocyte activity are also a pluripotent hematopoietic stem cell population, and the expression of c-kit on c-kit^<low cells is the first maturational step of hematopoiesis.

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