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Resolution of Unique Sca-1^highc-Kit^– Lymphoid-Biased Progenitors in Adult Bone Marrow¹

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

We have identified a distinctive lymphoid-restricted progenitor population in adult mouse bone marrow based on a unique c-Kit^–Sca-1^highFlt3⁺ AA4⁺ surface phenotype. These cells are highly lymphoid biased and rapidly generate B and T cells after adoptive transfer. However, whereas previously described lymphoid progenitors such as common lymphoid progenitors express TdT and relatively high levels of RAG2, and are enriched for cells with an active V(D)J recombinase, Flt3⁺ AA4⁺ cells within the c-Kit^–Sca-1^high bone marrow fraction are TdT^–, are RAG2^low, and do not display evidence for ongoing or past recombinase activity. Furthermore, unlike common lymphoid progenitors that readily generate B cells upon stimulation with IL-7, c-Kit^–Sca-1^highFlt3⁺ precursors do not express abundant levels of the IL-7R, and require costimulation with Flt3 ligand and IL-7 to generate B cells in vitro. Moreover, these findings suggest that hematopoietic stem cells in adults generate an array of lymphoid-biased progenitor populations characterized by distinct gene expression and cytokine response profiles.

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 AG546776 from the National Institutes of Health. D.A. is the recipient of a Career Development Award from the Leukemia and Lymphoma Society.

² Address correspondence and reprint requests to Dr. David Allman, Department of Pathology and Laboratory Medicine, 230 John Morgan Building, University of Pennsylvania School of Medicine, 36th and Hamilton Walk, Philadelphia, PA 19104-6082. E-mail address: dallman{at}mail.med.upenn.edu

³ Abbreviations used in this paper: MPP, multipotent progenitor; HSC, hematopoietic stem cell; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; LBP, lymphoid-biased progenitor; ELP, early lymphoid progenitor; LSK, Lin^–Sca-1⁺c-Kit^high; BM, bone marrow; SCF, stem cell factor.