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Hina Takano^1,2, Hideo Ema¹, Kazuhiro Sudo², and Hiromitsu Nakauchi^1,2

¹ Laboratory of Stem Cell Therapy, Center for Experimental Medicine, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
² Department of Immunology, Institute of Basic Medical Sciences, University of Tsukuba, 305-8575 Tsukuba, Japan

Address correspondence to Hiromitsu Nakauchi, Laboratory of Stem Cell Therapy, Center for Experimental Medicine, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639 Tokyo, Japan. Phone: 81-3-5449-5330; Fax: 81-3-5449-5451; email: nakauchi{at}ims.u-tokyo.ac.jp

How hematopoietic stem cells (HSCs) commit to a particular lineage is unclear. A high degree of HSC purification enabled us to address this issue at the clonal level. Single-cell transplantation studies revealed that 40% of the CD34^-/low, c-Kit⁺, Sca-1⁺, and lineage marker^- (CD34^-KSL) cells in adult mouse bone marrow were able, as individual cells, to reconstitute myeloid and B- and T-lymphoid lineages over the long-term. Single-cell culture showed that >40% of CD34^-KSL cells could form neutrophil (n)/macrophage (m)/erythroblast (E)/megakaryocyte (M) (nmEM) colonies. Assuming that a substantial portion of long-term repopulating cells can be detected as nmEM cells within this population, we compared differentiation potentials between individual pairs of daughter and granddaughter cells derived in vitro from single nmEM cells. One of the two daughter or granddaughter cells remained an nmEM cell. The other showed a variety of combinations of differentiation potential. In particular, an nmEM cell directly gave rise, after one cell division, to progenitor cells committed to nm, EM, or M lineages. The probability of asymmetric division of nmEM cells depended on the cytokines used. These data strongly suggest that lineage commitment takes place asymmetrically at the level of HSCs under the influence of external factors.

Key Words: hematopoiesis • cell differentiation • cell lineage • cell division • cytokines

Abbreviations used in this paper: bl, blastlike; CFC, colony-forming cell; CMP, common myeloid progenitor; E, erythroblast; EPO, erythropoietin; HSC, hematopoietic stem cell; m, macrophage; M, megakaryocyte; n, neutrophil; SA, streptavidin; SCF, stem cell factor; TPO, thrombopoietin.

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