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Soluble Frizzled-Related Protein 1 Is Estrogen Inducible in Bone Marrow Stromal Cells and Suppresses the Earliest Events in Lymphopoiesis¹

Takafumi Yokota^2,*, Kenji Oritani^*, Karla P. Garrett, Taku Kouro, Makoto Nishida, Isao Takahashi^*, Michiko Ichii^*, Yusuke Satoh^*, Paul W. Kincade and Yuzuru Kanakura^*

^* Department of Hematology and Oncology and Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104; and Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama City, Toyama, Japan

It has long been known that lymphopoiesis is transiently suppressed during pregnancy, which can be experimentally simulated by estrogen treatment. We now confirm with Rag1/GFP reporter mice that early lymphoid progenitors in the lineage marker^– c-kit^high ScaI⁺, hematopoietic stem cell-enriched fraction of bone marrow are particularly depressed in these circumstances. Hematopoietic and environmental cells are both potential hormone targets and, because of this complexity, very little is known regarding mechanisms. We have now identified soluble Frizzled-related protein (sFRP)1 as an estrogen-inducible gene in stromal cells, whose expression corresponded to inability to support lymphopoiesis. Bone-lining stromal cells express sFRP1, and the transcripts were elevated by pregnancy or estrogen injection. Estrogen receptor- was essential for both lymphoid suppression and induction of the sFRP family. SFRP1 has been mainly described as an antagonist for complex Wnt signals. However, we found that sFRP1, like Wnt3a, stabilized β-catenin and blocked early lymphoid progression. Myeloerythroid progenitors were less affected by sFRP1 in culture, which was similar to estrogen with respect to lineage specificity. Hematopoietic stem cells expressed various Frizzled receptors, which markedly declined as they differentiated to lymphoid lineage. Thus, hormonal control of early lymphopoiesis in adults might partly relate to sFRP1 levels.

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 partly supported by Grants AI20069 and AI058162 from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Takafumi Yokota, Department of Hematology and Oncology, Osaka University Graduate School of Medicine, C9, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail address: yokotat{at}bldon.med.osaka-u.ac.jp

³ Abbreviations used in this paper: HSC, hematopoietic stem cell; BIO, 6-bromoindirubin-37-oxime; BM, bone marrow; CLP, common lymphoid progenitor; CRD, cysteine-rich domain; ELP, early lymphoid progenitor; ER, estrogen receptor; LSK, Lin^– ScaI⁺ c-kit^high; MC, mesenchymal cell; MPP, multipotent progenitor; MSC, mesenchymal stem cell; sFRP, soluble Frizzled-related protein.