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* Division of Research Immunology and Bone Marrow Transplantation, Childrens Hospital Los Angeles, Los Angeles, CA 90027;
Department of Pathology and Human Anatomy and
Center for Health Disparities and Molecular Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 92350; and
Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Wisconsin at Madison, Madison, WI 53792
IL-7 is critical for B cell production in adult mice; however, its role in human B lymphopoiesis is controversial. One challenge was the inability to differentiate human cord blood (CB) or adult bone marrow (BM) hematopoietic stem cells (HSCs) without murine stroma. Here, we examine the role of IL-7 in human B cell development using a novel, human-only model based on coculturing human HSCs on primary human BM stroma. In this model, IL-7 increases human B cell production by >60-fold from both CB and adult BM HSCs. IL-7-induced increases are dose-dependent and specific to CD19+ cells. STAT5 phosphorylation and expression of the Ki-67 proliferation Ag indicate that IL-7 acts directly on CD19+ cells to increase proliferation at the CD34+ and CD34– pro-B cell stages. Without IL-7, HSCs in CB, but not BM, give rise to a small but consistent population of CD19lo B lineage cells that express EBF (early B cell factor) and PAX-5 and respond to subsequent IL-7 stimulation. Flt3 ligand, but not thymic stromal-derived lymhopoietin (TSLP), was required for the IL-7-independent production of human B lineage cells. As compared with CB, adult BM shows a reduction of in vitro generative capacity that is progressively more profound in developmentally sequential populations, resulting in an 
50-fold reduction in IL-7-dependent B lineage generative capacity. These data provide evidence that IL-7 is essential for human B cell production from adult BM and that IL-7-induced expansion of the pro-B compartment is increasingly critical for human B cell production during the progression of ontogeny.
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 the National Institutes of Health Grants K22 CA 111392 (to S.D.) and 5K01 DK066163 (to K.J.P.), a Research Career Development Award from the Saban Research Institute at Childrens Hospital Los Angeles (to K.J.P.), and the Center for Health Disparities and Molecular Medicine and the Department of Pathology and Human Anatomy, Loma Linda University (to K.J.P.).
2 Address correspondence and reprint requests to Dr. Kimberly J. Payne, Loma Linda University, 11085 Campus Street, Mortensen Hall, 1st floor, Loma Linda, CA 92350. E-mail address: kpayne{at}llu.edu
3 Abbreviations used in this paper: BM, bone marrow; EBF, early B cell factor; CB, umbilical cord blood; cµ, cytoplasmic µ; FSC, forward scatter; HSC, hematopoietic stem cell; Lin–, lineage marker negative; ND50, 50% neutralizing dose; TSLP, thymic stromal-derived lymphopoietin.
4 The online version of this article contains supplemental material.
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