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* Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, and
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104;
Laboratory for Lymphocyte Differentiation and Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa, Japan;
Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands; and
¶ Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worchester, MA 01655
The Wnt family of secreted glycoproteins has been implicated in many aspects of development, but its contribution to blood cell formation is controversial. We overexpressed Wnt3a, Wnt5a, and Dickkopf 1 in stromal cells from osteopetrotic mice and used them in coculture experiments with highly enriched stem and progenitor cells. The objective was to learn whether and how particular stages of B lymphopoiesis are responsive to these Wnt family ligands. We found that canonical Wnt signaling, through Wnt3a, inhibited B and plasmacytoid dendritic cell, but not conventional dendritic cell development. Wnt5a, which can oppose canonical signaling or act through a different pathway, increased B lymphopoiesis. Responsiveness to both Wnt ligands diminished with time in culture and stage of development. That is, only hematopoietic stem cells and very primitive progenitors were affected. Although Wnt3a promoted retention of hematopoietic stem cell markers, cell yields and dye dilution experiments indicated it was not a growth stimulus. Other results suggest that lineage instability results from canonical Wnt signaling. Lymphoid progenitors rapidly down-regulated RAG-1, and some acquired stem cell-staining characteristics as well as myeloid and erythroid potential when exposed to Wnt3a-producing stromal cells. We conclude that at least two Wnt ligands can differentially regulate early events in B lymphopoiesis, affecting entry and progression in distinct differentiation lineages.
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 in part by Grants AI 058162 and AI043544 from the National Institutes of Health, as well as private institutional funds.
2 Address correspondence and reprint requests to Paul W. Kincade, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK 73104.
3 Abbreviations used in this paper: Fzd, Frizzled; cDC, conventional dendritic cell; CLP, common lymphoid progenitor; Dkk, Dickkopf; ELP, early lymphoid progenitor; FL, Flk2/Flt3 ligand; HSC, hematopoietic stem cell; LRP, lipoprotein receptor-related protein; LSK, lineage marker negative, Sca-1 positive, c-Kit high; pDC, plasmacytoid dendritic cell; ProL, prolymphocyte; SCF, stem cell factor; TPO, thrombopoietin.
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