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TISSUE-SPECIFIC STEM CELLS

Identification of Long-Term Repopulating Potential of Human Cord Blood-Derived CD34^–flt3^– Severe Combined Immunodeficiency-Repopulating Cells by Intra-Bone Marrow Injection

^aDepartment of Stem Cell Biology and Regenerative Medicine, Graduate School of Medical Science, Kansai Medical University, Moriguchi, Osaka, Japan;
^bDepartment of Gynecology and Obstetrics, Fukuda Hospital, Kumamoto, Japan;
^cDepartment of Obstetrics and Gynecology, Aizenbashi Hospital, Osaka, Japan;
^dDepartment of Microbiology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto, Japan;
^eDepartment of Industrial Science and Technology, Tokyo University of Science, Noda, Chiba, Japan;
^fFirst Department of Pathology, Transplantation Center,
^gFirst Department of Internal Medicine, Kansai Medical University, Moriguchi, Osaka, Japan

Key Words. Flt3 • Severe combined immunodeficiency-repopulating cell • Intra-bone marrow injection • Cord blood • Hematopoiesis

Correspondence: Yoshiaki Sonoda, M.D., Department of Stem Cell Biology and Regenerative Medicine, Graduate School of Medical Science, Kansai Medical University, Moriguchi, Osaka 570-8506, Japan. Telephone: +81-6-6993-9435; Fax: +81-6-6992-3522; e-mail: sonoda{at}takii.kmu.ac.jp

Received November 8, 2006; accepted for publication February 6, 2007.
First published online in STEM CELLS EXPRESS   February 15, 2007.



Recently, we have identified human cord blood (CB)-derived CD34-negative (CD34^–) severe combined immunodeficiency (SCID)-repopulating cells (SRCs) using the intra-bone marrow injection (IBMI) method (Blood 2003;101:2924). In contrast to murine CD34^– Kit⁺Sca-1⁺Lineage^– (KSL) cells, human CB-derived Lin^–CD34^– cells did not express detectable levels of c-kit by flow cytometry. In this study, we have investigated the function of flt3 in our identified human CB-derived CD34^– SRCs. Both CD34⁺flt3^+/– cells showed SRC activity. In the CD34^– cell fraction, only CD34^–flt3^– cells showed distinct SRC activity by IBMI. Although CD34⁺flt3⁺ cells showed a rather weak secondary repopulating activity, CD34⁺flt3^– cells repopulated many more secondary recipient mice. However, CD34^–flt3^– cells repopulated all of the secondary recipients, and the repopulating rate was much higher. Next, we cocultured CD34^–flt3^– cells with the murine stromal cell line HESS-5. After 1 week, significant numbers of CD34⁺flt3^+/– cells were generated, and they showed distinct SRC activity. These results indicated that CB-derived CD34^–flt3^– cells produced CD34⁺flt3^– as well as CD34⁺flt3⁺ SRCs in vitro. The present study has demonstrated for the first time that CB-derived CD34^– SRCs, like murine CD34^– KSL cells, do not express flt3. On the basis of these data, we propose that the immunophenotype of very primitive long-term repopulating human hematopoietic stem cells is Lin^–CD34^–c-kit^–flt3^–.

Disclosure of potential conflicts of interest is found at the end of this article.

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