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Lin^–Sca1⁺Kit^– Bone Marrow Cells Contain Early Lymphoid-Committed Precursors That Are Distinct from Common Lymphoid Progenitors¹

Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029

The significance of a population in mouse bone marrow of lineage-negative (Lin^–), Sca1-positive, c-kit-negative (LSK^–) cells, which is reported to be devoid of long-term repopulation capacity or myeloid potential, is unknown. In this study, we show that the LSK^– population is composed of several subsets defined by the expression of flt3, CD25, and IL-7R. The first subset was CD25^– and more than 90% expressed either flt3, IL-7R, or both. The CD25^–LSK^– population had T cell, B cell, and NK cell potential in vivo, and most of this activity was localized in the flt3⁺ subset, irrespective of the expression of IL-7R. Although lymphoid potential of flt3⁺LSK^– cells in vivo was 3-fold lower than that of lin^–Sca1^lowkit^lowIL7R⁺ common lymphoid progenitors (CLPs), their cloning efficiency in vitro was 10-fold lower than that of CLPs. Furthermore, although the myeloid potential of flt3⁺LSK^– cells was 10-fold lower than that of CLPs in the absence of M-CSF, the relative myeloid potential of both populations was similar in its presence. These observations suggest differential growth factor requirements of both populations. The second subset of LSK^– cells was homogeneously CD25⁺flt3^–IL7R⁺ and could be generated from both CD25^–LSK^– cells and from CLPs, but did not engraft in immunodeficient Rag1^–/– or Rag1^–/–_c^–/– hosts. This population, of which the significance is unclear, was increased in Rag1^–/– mice and in old mice. Thus, the LSK^– population is phenotypically and functionally heterogeneous and contains early lymphoid-committed precursors. Our findings imply that the early stages of lymphoid commitment are more complex than was thus far assumed.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant R01 AG16327 from the National Institutes of Health (to H.W.S.).

² Address correspondence and reprint requests to Dr. Hans-Willem Snoeck, Department Gene and Cell Medicine, Mount Sinai School of Medicine, Box 1496, Gustave L. Levy Place, New York, NY 10029. E-mail address: hans.snoeck{at}mssm.edu

³ Abbreviations used in this paper: HSC, hematopoietic stem cell; CLP, common lymphoid progenitor; Lin, lineage; LSK^–, lin^–Sca1⁺kit^–; MPP, multipotential progenitor; ELP, early lymphoid progenitor; DN, double negative; Flt3L, Flt3 ligand; wt, wild type.